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GABAergic
Terms modified by GABAergic Selected AbstractsGenetic and pharmacological studies of GluR5 modulation of inhibitory synaptic transmission in the anterior cingulate cortex of adult miceDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2007Long-Jun Wu Abstract In the anterior cingulate cortex (ACC), GluR5-containing kainate receptor mediated the small portion of excitatory postsynaptic current. However, little is known about its role in modulation of neurotransmitter release in this brain region. In the present study, we address this question by using selective GluR5 agonist and antagonist, as well as GluR5,/, mice. Our results showed that activation of GluR5 induced action potential-dependent GABA release, which is also required for the activation of voltage-dependent calcium channel and Ca2+ influx. The effect of GluR5 activation is selective to the GABAergic, but not glutamatergic synaptic transmission. Endogenous activation of GluR5 also enhanced GABA release to ACC pyramidal neurons and the corresponding postsynaptic tonic GABA current. Our results suggest the somatodendritic, but not presynaptic GluR5, in modulation of GABA release. The endogenous GluR5 activation and the subsequent tonic GABA current may play an inhibitory role in ACC-related brain functions. © 2006 Wiley Periodicals, Inc. Develop Neurobiol 67: 146,157, 2007. [source] Post-traumatic stress disorder: a review of psychobiology and pharmacotherapyACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2001I. Hageman Objective: To review the literature on the psychobiology and pharmacotherapy of PTSD. Method: Relevant studies were identified by literature searches (Pub-med, web of science) and through reference lists. The search was ended by May 2001. Results: There is evidence of involvement of opioid, glutamatergic, GABAergic, noradrenergic, serotonergic and neuroendocrine pathways in the pathophysiology of PTSD. Medications shown to be effective in double-blind placebo-controlled trials includes selective serotonin reuptake inhibitors, reversible and irreversible MAO-inhibitors, tricyclic antidepressants and the anticonvulsant lamotrigine. Still more agents appear promising in open-label trials. Conclusion: The complexity of the psychobiology is reflected by the difficulties in treating the disorder. According to the present knowledge, suggestions for drug treatment of PTSD are made. [source] Approaches to the development of medications for the treatment of methamphetamine dependenceADDICTION, Issue 2007Frank J. Vocci ABSTRACT Background Methamphetamine abuse has become an increasing problem in both the United States and globally with concomitant increases in adverse medical, social and environmental sequelae. Behavioral therapies have been used with some success to treat methamphetamine abusers and dependent individuals, but are not universally efficacious. Methamphetamine has a rich pharmacology that theoretically provides many opportunities for potential pharmacotherapeutic intervention. Nevertheless, there are no approved medications with an indication for treating methamphetamine abusers or addicts at this time. Aim To describe briefly how methamphetamine functions and affects function in brain and report how basic researchers and clinicians are attempting to exploit and exploiting this knowledge to discover and develop effective pharmacotherapies. Results Scientifically based approaches to medications development by evaluating medications that limit brain exposure to methamphetamine; modulate methamphetamine effects at vesicular monoamine transporter-2 (VMAT-2); or affect dopaminergic, serotonergic, GABAergic, and/or glutamatergic brain pathways that participate in methamphetamine's reinforcing effects are presented. Conclusion The evidence supports the rationale that pharmacotherapies to decrease methamphetamine use, or reduce craving during abstinence may be developed from altering the pharmacokinetics and pharmacodynamics of methamphetamine or its effects on appetitive systems in the brain. [source] REVIEW: The alcohol-preferring P rat and animal models of excessive alcohol drinkingADDICTION BIOLOGY, Issue 3-4 2006Richard L. Bell ABSTRACT The alcohol-preferring, P, rat was developed by selective breeding to study ethanol drinking behavior and its consequences. Characterization of this line indicates the P rat meets all of the criteria put forth for a valid animal model of alcoholism, and displays, relative to their alcohol-non-preferring, NP, counterparts, a number of phenotypic traits associated with alcohol abuse and alcoholism. Behaviorally, compared with NP rats, P rats are less sensitive to the sedative and aversive effects of ethanol and more sensitive to the stimulatory effects of ethanol. Neurochemically, research with the P line indicates the endogenous dopaminergic, serotonergic, GABAergic, opiodergic, and peptidergic systems may be involved in a predisposition for alcohol abuse and alcoholism. Paralleling the clinical literature, genetically selected P rats display levels of ethanol intake during adolescence comparable to that seen during adulthood. Binge drinking has been associated with an increased risk for health and other problems associated with ethanol abuse. A model of binge-like drinking during the dark cycle indicates that P rats will consume 6 g/kg/day of ethanol in as little as three 1-hour access periods/day, which approximates the 24-hour intake of P rats with free-choice access to a single concentration of ethanol. The alcohol deprivation effect (ADE) is a transient increase in ethanol intake above baseline values upon re-exposure to ethanol access after an extended period of deprivation. The ADE has been proposed to be an animal model of relapse behavior, with the adult P rat displaying a robust ADE after prolonged abstinence. Overall, these findings indicate that the P rat can be effectively used in models assessing alcohol-preference, a genetic predisposition for alcohol abuse and/or alcoholism, and excessive drinking using protocols of binge-like or relapse-like drinking. [source] Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanismsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009V. I. Chefer Abstract Mu opioid receptor (MOR) regulation of somatodendritic dopamine neurotransmission in the ventral tegmental area (VTA) was investigated using conventional microdialysis in freely moving rats and mice. Reverse dialysis of the MOR agonist DAMGO (50 and 100 ,m) into the VTA of rats produced a concentration-dependent increase in dialysate dopamine concentrations. Basal dopamine overflow in the VTA was unaltered in mice lacking the MOR gene. However, basal ,-aminobutyric acid (GABA) overflow in these animals was significantly increased, whereas glutamate overflow was decreased. Intra-VTA perfusion of DAMGO into wild-type (WT) mice increased dopamine overflow. GABA concentrations were decreased, whereas glutamate concentrations in the VTA were unaltered. Consistent with the loss of MOR, no effect of DAMGO was observed in MOR knockout (KO) mice. These data provide the first direct demonstration of tonically active MOR systems in the VTA that regulate basal glutamatergic and GABAergic neurotransmission in this region. We hypothesize that increased GABAergic neurotransmission following constitutive deletion of MOR is due to the elimination of a tonic inhibitory influence of MOR on GABAergic neurons in the VTA, whereas decreased glutamatergic neurotransmission in MOR KO mice is a consequence of intensified GABA tone on glutamatergic neurons and/or terminals. As a consequence, somatodendritic dopamine release is unaltered. Furthermore, MOR KO mice do not exhibit the positive correlation between basal dopamine levels and the glutamate/GABA ratio observed in WT mice. Together, our findings indicate a critical role of VTA MOR in maintaining an intricate balance between excitatory and inhibitory inputs to dopaminergic neurons. [source] Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cordEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007Line Lundfald Abstract The ventral spinal cord consists of interneuron groups arising from distinct, genetically defined, progenitor domains along the dorsoventral axis. Many of these interneuron groups settle in the ventral spinal cord which, in mammals, contains the central pattern generator for locomotion. In order to better understand the locomotor networks, we have used different transgenic mice for anatomical characterization of one of these interneuron groups, called V2 interneurons. Neurons in this group are either V2a interneurons marked by the postmitotic expression of the transcription factor Chx10, or V2b interneurons which express the transcription factors Gata2 and Gata3. We found that all V2a and most V2b interneurons were ipsilaterally projecting in embryos as well as in newborns. V2a interneurons were for the most part glutamatergic while V2b interneurons were mainly GABAergic or glycinergic. Furthermore, we demonstrated that a large proportion of V2 interneurons expressed the axon guidance molecule EphA4, a molecule previously shown to be important for correct organization of locomotor networks. We also showed that V2 interneurons and motor neurons alone did not account for all EphA4-expressing neurons in the spinal cord. Together, these findings enable a better interpretation of neural networks underlying locomotion, and open up the search for as yet unknown components of the mammalian central pattern generator. [source] Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapsesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Elaine C. Budreck Abstract Synaptic adhesion molecules are thought to play a critical role in the formation, function and plasticity of neuronal networks. Neuroligins (NL1,4) are a family of presumptive postsynaptic cell adhesion molecules. NL1 and NL2 isoforms are concentrated at glutamatergic and GABAergic synapses, respectively, but the cellular expression and synaptic localization of the endogenous NL3 and NL4 isoforms are unknown. We generated a panel of NL isoform-specific antibodies and examined the expression, developmental regulation and synaptic specificity of NL3. We found that NL3 was enriched in brain, where NL3 protein levels increased during postnatal development, coinciding with the peak of synaptogenesis. Subcellular fractionation revealed a concentration of NL3 in synaptic plasma membranes and postsynaptic densities. In cultured hippocampal neurons, endogenous NL3 was highly expressed and was localized at both glutamatergic and GABAergic synapses. Clustering of NL3 in hippocampal neurons by neurexin-expressing cells resulted in coaggregation of NL3 with glutamatergic and GABAergic scaffolding proteins. Finally, individual synapses contained colocalized NL2 and NL3 proteins, and coimmunoprecipitation studies revealed the presence of NL1,NL3 and NL2,NL3 complexes in brain extracts. These findings suggest that rodent NL3 is a synaptic adhesion molecule that is a shared component of glutamatergic and GABAergic synapses. [source] GABAergic projections from the hippocampus to the retrosplenial cortex in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007Toshio Miyashita Abstract The retrosplenial cortex (RS) in rats has been implicated in a wide range of behaviors, including spatial navigation and memory. Relevant to this, the RS is closely interconnected with the hippocampus by multiple direct and indirect routes. Here, by injecting the retrograde tracer cholera toxin subunit B conjugated with Alexa488 (CTB-Alexa488) in the granular retrosplenial cortex (GRS), we demonstrate a moderately dense non-pyramidal projection from CA1. Neurons are in several layers, but mainly (about 65%) at the border of the stratum radiatum (SR) and stratum lacunosum moleculare (SLM). In particular, by double-labeling with GAD67 or ,-aminobutyric acid (GABA), we establish that these neurons are GABAergic. Further immunocytochemical screening for calcium-binding proteins, somatostatin (SS) or cholecystokinin (CCK) failed to identify additional neurochemical subgroups; but a small subset (about 14%) is positive for the m2 muscarinic acetylcholine receptor (M2R). Terminations target layer 1 of the GRS, as shown by biotinylated dextran amine (BDA) injections into CA1 and confirmed by a very superficial injection of CTB-Alexa488 in GRS. The superficial injection shows that there is a sparse GABAergic projection from the subiculum to layer 1 of the GRS, in addition to the dense excitatory connections to layer 3. The role of these dual inhibitory,excitatory pathways , within the subiculum, and in parallel from CA1 and the subiculum , remains to be determined, but may be related to synchronized oscillatory activity in the hippocampal complex and GRS, or to the generation of rhythmic activity within the GRS. [source] Altered neuronal responses and regulation of neurotrophic proteins in the medial septum following fimbria-fornix transection in CNTF- and leukaemia inhibitory factor-deficient miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2006Thomas Naumann Abstract Degeneration of axotomized GABAergic septohippocampal neurones has been shown to be enhanced in ciliary neurotrophic factor (CNTF)-deficient mice following fimbria-fornix transection (FFT), indicating a neuroprotective function of endogenous CNTF. Paradoxically, however, the cholinergic population of septohippocampal neurones was more resistant to axotomy in these mutants. As leukaemia inhibitory factor (LIF) has been identified as a potential neuroprotective factor for the cholinergic medial septum (MS) neurones, FFT-induced responses were compared in CNTF,/,, LIF,/, and CNTF/LIF double knockout mice. In CNTF,/, mice, FFT-induced cholinergic degeneration was confirmed to be attenuated as compared with wildtype mice. The expression of both LIF and LIF receptor , was increased in the MS providing a possible explanation for the enhanced neuronal resistance to FFT in these animals. However, ablation of the LIF gene also produced paradoxical effects; following FFT in LIF,/, mice no loss of GABAergic or cholinergic MS neurones was detectable during the first postlesional week, suggesting that other efficient neuroprotective mechanisms are activated in these animals. In fact, enhanced activation of astrocytes, a source of neurotrophic proteins, was indicated by increased up-regulation of glial fibrillary acidic protein and vimentin expression. In addition, mRNA levels for neurotrophin signalling components (e.g. nerve growth factor, p75NTR) were differentially regulated. The positive effect on axotomized cholinergic neurones seen in CNTF,/, and LIF,/, mice as well as the increased up-regulation of astrogliose markers was abolished in CNTF/LIF double knockout animals. Our results indicate that endogenous CNTF and LIF are involved in the regulation of neuronal survival following central nervous system lesion and are integrated into a network of neurotrophic signals that mutually influence their expression and function. [source] Muscarine activates the sodium,calcium exchanger via M3 receptors in basal forebrain neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2006Changqing Xu Abstract Neurons of the medial septum/diagonal band of Broca (MSDB) project to the hippocampus. Muscarinic cholinergic mechanisms within the MSDB are potent modulators of hippocampal functions; intraseptal scopolamine disrupts and intraseptal carbachol facilitates hippocampus-dependent learning and memory tasks, and the associated hippocampal theta rhythm. In earlier work, we demonstrated that, within the MSDB, the septohippocampal GABAergic but not cholinergic neurons are the primary target of muscarinic manipulations and that muscarinic activation of septohippocampal GABAergic neurons is mediated directly via M3 receptors. In the present study, we examined the ionic mechanism(s) underlying the excitatory actions of muscarine in these neurons. Using whole-cell patch-clamp recording techniques in rat brain slices, we demonstrated that M3 receptor-mediated muscarinic activation of MSDB neurons is dependent on external Na+ and is also reduced by bath-applied Ni2+ and KB-R7943 as well as by replacing external Na+ with Li+, suggesting a primary involvement of the Na+,Ca2+ exchanger. We conclude that the M3 receptor-mediated muscarinic activation of MSDB septohippocampal GABA-type neurons, that is important for cognitive functioning, is mediated via activation of the Na+,Ca2+ exchanger. [source] Pre- and postsynaptic GABAA receptors at reciprocal dendrodendritic synapses in the olfactory bulbEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2004Patrizia Panzanelli Abstract Presynaptic ionotropic receptors are important regulators of synaptic function; however, little is known about their organization in the presynaptic membrane. We show here a different spatial organization of presynaptic and postsynaptic GABAA receptors at reciprocal dendrodendritic synapses between mitral and granule cells in the rat olfactory bulb. Using postembedding electron microscopy, we have found that mitral cell dendrites express GABAA receptors at postsynaptic specializations of symmetric (GABAergic) synapses, as well as at presynaptic sites of asymmetric (glutamatergic) synapses. Analysis of the subsynaptic distribution of gold particles revealed that in symmetric synapses GABAA receptors are distributed along the entire postsynaptic membrane, whereas in asymmetric synapses they are concentrated at the edge of the presynaptic specialization. To assess the specificity of immunogold labelling, we analysed the olfactory bulbs of mutant mice lacking the ,1 subunit of GABAA receptors. We found that in wild-type mice ,1 subunit immunoreactivity was similar to that observed in rats, whereas in knockout mice the immunolabelling was abolished. These results indicate that in mitral cell dendrites GABAA receptors are distributed in a perisynaptic domain that surrounds the presynaptic specialization. Such presynaptic receptors may be activated by spillover of GABA from adjacent inhibitory synapses and modulate glutamate release, thereby providing a novel mechanism regulating dendrodendritic inhibition in the olfactory bulb. [source] Inhibition of superior colliculus neurons by a GABAergic input from the pretectal nuclear complex in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2004Gesche Born Abstract The mammalian pretectal nuclear complex (PNC) is a visual and visuomotor control structure which is strongly connected to other subcortical visual structures. This indicates that the PNC also controls subcortical visual information flow during the execution of various oculomotor programs. A prominent, presumably GABAergic, projection from the PNC targets the superficial grey layer of the superior colliculus (SC), which itself is a central structure for visual information processing necessary for the generation of saccadic eye movements. In order to characterize the pretecto-tectal projection in vitro, we performed whole-cell patch-clamp recordings from SC and PNC neurons in slices obtained from 3,6-week-old pigmented rats. Focal glutamate injections into the PNC and electrical PNC stimulation were used to induce postsynaptic responses in SC neurons. Electrical stimulation of the SC allowed electrophysiological identification of PNC neurons that provide the inhibitory pretecto-tectal input. Only inhibitory postsynaptic currents could be elicited in SC neurons both by pharmacological and by electrical activation of the ipsilateral PNC. Concomitantly, a small number of PNC neurons could be antidromically activated from the ipsilateral SC. Most SC cells postsynaptic to the prectectal input showed the dendritic morphology of wide-field and narrow-field cells and are therefore regarded as projection neurons. All inhibitory currents evoked by PNC activation could be completely blocked by bath application of the selective GABAA receptor antagonist bicuculline. Together these results indicate that SC projection neurons receive a direct inhibitory input from the ipsilateral PNC and that this input is mediated by GABAA receptors. [source] Activity-dependent modulation of GABAergic synapses in developing rat spinal networks in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Marcelo Rosato-Siri Abstract The role of activity-dependent plasticity in modulating inhibitory synapses was investigated in embryonic rat spinal cord slice cultures, by chronic exposure to non-NMDA receptor blockers. GABAergic synaptic efficacy in control and chronic-treated cultures was investigated by patch-recordings from visually identified spinal interneurons. In both culture groups proximal stimulation induced the appearance of postsynaptic currents (PSCs), which were fully antagonized by 20 µM bicuculline application and reverse polarity at potential values close to those reported for spontaneous GABAergic PSCs. In chronically treated cells GABAergic evoked PSCs displayed a larger failure rate and a smaller coefficient of variation of mean PSC amplitude, when compared to controls. As opposed to controls, chronic GABAergic evoked PSCs did not facilitate upon paired-pulse stimulation. Facilitation at chronic synapses was observed when extracellular calcium levels were decreased below physiological values (< 2 mM). Kainate was used to disclose any functional differences between control and treated slices. In accordance with the presynaptic action of kainate, the application of this drug along with GYKI, an AMPA receptor selective antagonist, changed, with analogous potency, short-term plasticity of GABAergic synapses from control and treated cultures. Nevertheless, in chronic cultures, the downstream effects of such activation unmasked short-term depression. Ultrastructural analysis of synapses in chronically treated cultures showed a reduction both in symmetric synapses and in the number of vesicles at symmetric terminals. Thus, based on electrophysiological and ultrastructural data, it could be suggested that during the development of spinal circuits, GABAergic synapses are modulated by glutamatergic transmission, and thus implying that excitatory transmission regulates the strength of GABAergic synapses. [source] The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projectionsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Martin Sarter Abstract At least half of the basal forebrain neurons which project to the cortex are GABAergic. Whilst hypotheses about the attentional functions mediated by the cholinergic component of this corticopetal projection system have been substantiated in recent years, knowledge about the functional contributions of its GABAergic branch has remained extremely scarce. The possibility that basal forebrain GABAergic neurons that project to the cortex are selectively contacted by corticofugal projections suggests that the functions of the GABAergic branch can be conceptualized in terms of mediating executive aspects of cognitive performance, including the switching between multiple input sources and response rules. Such speculations gain preliminary support from the effects of excitotoxic lesions that preferentially, but not selectively, target the noncholinergic component of the basal forebrain corticopetal system, on performance in tasks involving demands on cognitive flexibility. Progress in understanding the cognitive functions of the basal forebrain system depends on evidence regarding its main noncholinergic components, and the generation of such evidence is contingent on the development of methods to manipulate and monitor selectively the activity of the GABAergic corticopetal projections. [source] Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2000G. Rammes Abstract Electrophysiological and behavioural experiments were performed in transgenic mice expressing a dominant-negative form of cAMP response element-binding protein (CREBA133) in the limbic system. In control littermate in vitro slice preparation, tetanizing the lateral amygdala,basolateral amygdala (BLA) pathway with a single train (100 Hz for 1 s) produced short-term potentiation (STP) in the BLA. Five trains (10-s interstimulus interval) induced long-term potentiation (LTP), which was completely blocked by the N-methyl- d -aspartate (NMDA) receptor antagonist d(,)-2-amino-5-phosphonopentanoic acid (AP5; 50 ,m). When GABAergic (,-aminobutyric acid) inhibition was blocked by picrotoxin (10 ,m), LTP became more pronounced. Low-frequency stimulation (1 Hz for 15 min) induced either long-term depression (LTD) or depotentiation. LTD remained unaffected by AP5 (50 ,m) or by the L- and T-type Ca2+ -channel blockers nifedipine (20 ,m) and Ni2+ (50 ,m), but was prevented by picrotoxin (10 ,m), indicating a GABAergic link in the expression of LTD in the BLA. When conditioned fear was tested, a mild impairment was seen in one of three transgenic lines only. Although high levels of mRNA encoding CREBA133 lead to downregulation of endogenous CREB, expression of LTP and depotentiation were unaltered in BLA of these transgenic animals. These results could suggest that residual CREB activity was still present or that CREB per se is dispensable. Alternatively, other CREB-like proteins were able to compensate for impaired CREB function. [source] 5-HT1A and NMDA receptors interact in the rat medial septum and modulate hippocampal-dependent spatial learningHIPPOCAMPUS, Issue 12 2009Elin Elvander-Tottie Abstract Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT1A receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT1A receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT1A receptor agonist (R)-8-OH-DPAT (1 or 4 ,g/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 ,g/rat). While intraseptal administration of (R)-8-OH-DPAT (4 ,g) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 ,g) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT1A receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT1A and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT1A receptor activation on memory, which may be clinically relevant. © 2009 Wiley-Liss, Inc. [source] Secondary neurogenesis and telencephalic organization in zebrafish and mice: a brief reviewINTEGRATIVE ZOOLOGY (ELECTRONIC), Issue 1 2009Mario F. WULLIMANN Abstract Most zebrafish neurodevelopmental studies have focused on the embryo, which is characterized by primary neurogenesis of mostly transient neurons. Secondary neurogenesis becomes dominant in the hatching larva, when major brain parts are established and begin to differentiate. This developmental period allows for a comparative analysis of zebrafish brain organization with amniotes at equivalent stages of neurogenesis. Within a particular time window, the early forebrains of mice (Embyronic stage [E] 12.5/13.5 days [d]) and zebrafish (3 d) reveal highly comparable expression patterns of genes involved in neurogenesis, for example proneural and other transcription factors (Neurogenin1, NeuroD, Mash1/Zashla and Pax6). Further topological correspondences are seen in the expression of LIM and homeobox genes, such as Lhx6/7, Tbr2 and Dlx2a. When this analysis is extended to gamma-aminobutyric acid/glutamic acid decarboxylase (GABA/GAD) cell patterns during this critical time window, an astonishing degree of similarity between the two species is again seen, for example regarding the presence of GABA/GAD cells in the subpallium, with the pallium only starting to be invaded by such cells from the subpallium. Furthermore, the expression of proneural and other genes correlates with GABA cell patterns (e.g. Mash1/Zash1a gene expression in GABA-positive and Neurogenin1/NeuroD in GABA-negative telencephalic regions) in mice and zebrafish. Data from additional vertebrates, such as Xenopus, are also highly consistent with this analysis. Therefore, the vertebrate forebrain appears to undergo a phylotypic stage of secondary neurogenesis, characterized by regionally separated GABAergic (inhibitory) versus glutamatergic (excitatory) cell production sites, which are obscured later in development by tangential migration. This period is highly advantageous for molecular neuroanatomical cross-species comparisons. [source] Pre-synaptic BK channels selectively control glutamate versus GABA release from cortical and hippocampal nerve terminalsJOURNAL OF NEUROCHEMISTRY, Issue 2 2010Maria Martire J. Neurochem. (2010) 115, 411,422. Abstract In the present study, by means of genetic, biochemical, morphological, and electrophysiological approaches, the role of large-conductance voltage- and Ca2+ -dependent K+ channels (BK channels) in the release of excitatory and non-excitatory neurotransmitters at hippocampal and non-hippocampal sites has been investigated. The results obtained show that the pharmacological modulation of pre-synaptic BK channels selectively regulates [3H]d -aspartate release from cortical and hippocampal rat synaptosomes, but it fails to influence the release of excitatory neurotransmitters from cerebellar nerve endings or that of [3H]GABA, [3H]Noradrenaline, or [3H]Dopamine from any of the brain regions investigated. Confocal immunofluorescence experiments in hippocampal or cerebrocortical nerve terminals revealed that the main pore-forming BK , subunit was more abundantly expressed in glutamatergic (vGLUT1+) versus GABAergic (GAD65-67+) nerve terminals. Double patch recordings in monosynaptically connected hippocampal neurons in culture confirmed a preferential control exerted by BK channels on glutamate over GABA release. Altogether, the present results highlight a high degree of specificity in the regulation of the release of various neurotransmitters from distinct brain regions by BK channels, supporting the concept that BK channel modulators can be used to selectively limit excessive excitatory amino acid release, a major pathogenetic mechanism in several neuropsychiatric disorders. [source] The glutamatergic nature of TRPV1-expressing neurons in the spinal dorsal hornJOURNAL OF NEUROCHEMISTRY, Issue 1 2009Hong-Yi Zhou Abstract The transient receptor potential vanilloid receptor 1 (TRPV1) is expressed on primary afferent terminals and spinal dorsal horn neurons. However, the neurochemical phenotypes and functions of TRPV1-expressing post-synaptic neurons in the spinal cord are not clear. In this study, we tested the hypothesis that TRPV1-expressing dorsal horn neurons are glutamatergic. Immunocytochemical labeling revealed that TRPV1 and vesicular glutamate transporter-2 were colocalized in dorsal horn neurons and their terminals in the rat spinal cord. Resiniferatoxin (RTX) treatment or dorsal rhizotomy ablated TRPV1-expressing primary afferents but did not affect TRPV1- and vesicular glutamate transporter-2-expressing dorsal horn neurons. Capsaicin significantly increased the frequency of glutamatergic spontaneous excitatory post-synaptic currents and miniature excitatory post-synaptic currents in almost all the lamina II neurons tested in control rats. In RTX-treated or dorsal rhizotomized rats, capsaicin still increased the frequency of spontaneous excitatory post-synaptic currents and miniature excitatory post-synaptic currents in the majority of neurons examined, and this effect was abolished by a TRPV1 blocker or by non-NMDA receptor antagonist. In RTX-treated or in dorsal rhizotomized rats, capsaicin also produced an inward current in a subpopulation of lamina II neurons. However, capsaicin had no effect on GABAergic and glycinergic spontaneous inhibitory post-synaptic currents of lamina II neurons in RTX-treated or dorsal rhizotomized rats. Collectively, our study provides new histological and functional evidence that TRPV1-expressing dorsal horn neurons in the spinal cord are glutamatergic and that they mediate excitatory synaptic transmission. This finding is important to our understanding of the circuitry and phenotypes of intrinsic dorsal horn neurons in the spinal cord. [source] Molecular regulation of cognitive functions and developmental plasticity: impact of GABAA receptorsJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Hanns Möhler Abstract By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in regulating neuronal circuits and behavior. The pronounced diversity of GABAergic (,-aminobutyric acid) interneurons is paralleled by an extensive diversity of GABAA receptor subtypes. The region- and domain-specific location of these receptor subtypes offers the opportunity to gain functional insights into the role of defined neuronal circuits. These developments are reviewed with regard to the regulation of sleep, anxiety, memory, sensorimotor processing and post-natal developmental plasticity. [source] Human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal ratsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2006Therése Kallur Abstract Human fetal brain is a potential source of neural stem cells (NSCs) for cell replacement therapy in neurodegenerative diseases. We explored whether NSCs isolated from cortex and striatum of human fetuses, aged 6,9 weeks post-conception, maintain their regional identity and differentiate into specific neuron types in culture and after intrastriatal transplantation in neonatal rats. We observed no differences between cortex- and striatum-derived NSCs expanded as neurospheres in proliferative capacity, growth rate, secondary sphere formation, and expression of neural markers. After 4 weeks of differentiation in vitro, cortical and striatal NSCs gave rise to similar numbers of GABAergic and VMAT2- and parvalbumin-containing neurons. However, whereas cortical NSCs produced higher number of glutamatergic and tyrosine hydroxylase- and calretinin-positive neurons, several-fold more neurons expressing the striatal projection neuron marker, DARPP-32, were observed in cultures of striatal NSCs. Human cortical and striatal NSCs survived and migrated equally well after transplantation. The two NSC types also generated similar numbers of mature NeuN-positive neurons, which were several-fold higher at 4 months as compared to at 1 month after grafting. At 4 months, the grafts contained cells with morphologic characteristics of neurons, astrocytes, and oligodendrocytes. Many of neurons were expressing parvalbumin. Our data show that NSCs derived from human fetal cortex and striatum exhibit region-specific differentiation in vitro, and survive, migrate, and form mature neurons to the same extent after intrastriatal transplantation in newborn rats. © 2006 Wiley-Liss, Inc. [source] Differential Effects of Ethanol on Serum GABAergic 3,,5,/3,,5, Neuroactive Steroids in Mice, Rats, Cynomolgus Monkeys, and HumansALCOHOLISM, Issue 3 2010Patrizia Porcu Background:, Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3,,5,)-3-hydroxypregnan-20-one (3,,5,-THP) and (3,,5,)-3,21-dihydroxypregnan-20-one (3,,5,-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3,,5,- and 3,,5,-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. Methods:, Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results:, Ethanol administration to rats increased levels of 3,,5,-THP, 3,,5,-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3,,5,-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. Conclusions:, These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses. [source] Impact of Sex: Determination of Alcohol Neuroadaptation and ReinforcementALCOHOLISM, Issue 2 2006Kristine M. Wiren This article represents the proceedings of a symposium at the Research Society on Alcoholism meeting in Santa Barbara, California. The organizers/chairs were Kristine M. Wiren and Deborah A. Finn. Following a brief introduction by Deborah Finn, the presentations were (1) The Importance of Gender in Determining Expression Differences in Mouse Lines Selected for Chronic Ethanol Withdrawal Severity, by Kristine M. Wiren and Joel G. Hashimoto; (2) Sex Differences in Ethanol Withdrawal Involve GABAergic and Stress Systems, by Paul E. Alele and Leslie L. Devaud; (3) The Influence of Sex on Ethanol Consumption and Reward in C57BL/6 Mice, by Kimber L. Price and Lawrence D. Middaugh; and (4) Sex Differences in Alcohol Self-administration in Cynomolgus Monkeys, by Kathleen A. Grant. [source] Differential localization of carbachol- and bicuculline-sensitive pontine sites for eliciting REM sleep-like effects in anesthetized ratsJOURNAL OF SLEEP RESEARCH, Issue 1 2009VICTOR B. FENIK Summary Carbachol, a cholinergic agonist, and GABAA receptor antagonists injected into the pontine dorsomedial reticular formation can trigger rapid eye movement (REM) sleep-like state. Data suggest that GABAergic and cholinergic effects interact to produce this effect but the sites where this occurs have not been delineated. In urethane-anesthetized rats, in which carbachol effectively elicits REM sleep-like episodes (REMSLE), we tested the ability of 10 nL microinjections of carbachol (10 mm) and bicuculline (0.5 or 2 mm) to elicit REMSLE at 47 sites located within the dorsal pontine reticular formation at the levels -8.00 to -10.80 from bregma (B) (Paxinos and Watson, The Rat Brain in Stereotaxic Coordinates, Academic Press, San Diego, 1997). At rostral levels, most carbachol and some bicuculline injections elicited REMSLE with latencies that gradually decreased from 242 to 12 s for carbachol and from 908 to 38 s for bicuculline for more caudal injection sites. As the latencies decreased, the durations of bicuculline-elicited REMSLE increased from 104 s to over 38 min, and the effect was dose dependent, whereas the duration of carbachol-elicited REMSLE changed little (104,354 s). Plots of REMSLE latency versus the antero-posterior coordinates revealed that both drugs were maximally effective near B-8.80. At levels caudal to B-8.80, carbachol was effective at few sites, whereas bicuculline-elicited REMSLE to at least B-9.30 level. Thus, the bicuculline-sensitive sites extended further caudally than those for carbachol and antagonism of GABAA receptors both triggered REMSLE and controlled their duration, whereas carbachol effects on REMSLE duration were small or limited by its concurrent REMSLE-opposing actions. [source] Differential Adaptations in GABAergic and Glutamatergic Systems During Ethanol Withdrawal in Male and Female RatsALCOHOLISM, Issue 6 2005P E. Alele Background: There are significant and consistent sex differences in recovery from ethanol withdrawal in our animal model of ethanol dependence. We have also observed significant and varied sex differences in subunit protein levels of ,-aminobutyric acid A (GABAA) and the N-metheyl-D-aspartate subtype of glutamate receptors occurring with ethanol dependence and withdrawal. Considering the major role of these two systems as targets of ethanol, we wanted to explore additional possible mechanisms underlying changes in GABAergic and glutamatergic responses after chronic ethanol exposure. Therefore, the objective of the present study was to examine GABAergic- and glutamatergic-associated proteins at three days of ethanol withdrawal, when female rats appear to have largely recovered but male rats still display robust signs of withdrawal. Methods: Male and female rats were fed 6% ethanol in a nutritionally complete liquid diet for 14 days according to a pair-fed design; withdrawal was initiated by replacement of the diet with chow. At three days of withdrawal, the cerebral cortex and hippocampus were dissected for use in Western blot analysis. The paired design was maintained throughout all experimental procedures. Results: At three days of ethanol withdrawal, we found region-specific and sex-selective alterations in levels of GAD (glutamic acid decarboxylase, GABA synthetic enzyme), GABA and glutamate transporters, and the synapse-associated proteins HSP70, PSD-95, and synaptophysin. There were also several significant differences in transporter function at this time that varied between males and females. Conclusions: Taken together, these findings show differential adaptations of GABAergic and glutamatergic neurotransmission between female and male rats that are associated with withdrawal recovery. This suggests that selective withdrawal-induced neuroadaptations in regulation of these systems' activities underlie, at least in part, sex differences in withdrawal recovery between male and female rats. [source] Ethanol Dependence Has Limited Effects on GABA or Glutamate Transporters in Rat BrainALCOHOLISM, Issue 4 2001Leslie L. Devaud Background: Neuroadaptations of GABAergic and glutamatergic systems appear to play an important role in both the acute as well as chronic effects of ethanol. Chronic ethanol intake leads to the development of ethanol tolerance and dependence that is associated with a decrease in GABAergic and an increase in glutamatergic function. The present report assessed the involvement of GABA and glutamate transporters in the chronic ethanol-induced adaptations of these two neuronal systems. Methods: Male and female rats were made ethanol dependent by 2-week administration of ethanol in a liquid diet. Levels of GABA (GAT-1, GAT-3) and glutamate (GLT-1, EAAC-1) transporters were assayed by immunoblotting. Transporter function was assessed by [3H]GABA and [3H]glutamate uptake assays. Results: Ethanol dependence did not alter levels of GABA or glutamate transporters in cerebral cortex compared with pair-fed control values. There were increases in some, but not all, transporter levels in hippocampus and hypothalamus with the development of ethanol dependence. A decreased rate of uptake was observed for GABA in cerebral cortex. There was no change in maximal GABA uptake or in glutamate uptake (Vmax). Conclusions: These results suggest that alterations in GABA and glutamate transporters have only a limited role in neuroadaptations to chronic ethanol intake in rats. However, the observed alterations were region-specific, supporting the complex responses to chronic ethanol exposure and suggesting that neuroadaptations of GABAergic and glutamatergic systems vary across the brain. [source] Peripheral synaptic contacts at mechanoreceptors in arachnids and crustaceans: Morphological and immunocytochemical characteristicsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 4 2002Ruth Fabian-Fine Abstract Two types of sensory organs in crustaceans and arachnids, the various mechanoreceptors of spiders and the crustacean muscle receptor organs (MRO), receive extensive efferent synaptic innervation in the periphery. Although the two sensory systems are quite different,the MRO is a muscle stretch receptor while most spider mechanoreceptors are cuticular sensilla,this innervation exhibits marked similarities. Detailed ultrastructural investigations of the synaptic contacts along the mechanosensitive neurons of a spider slit sense organ reveal four important features, all having remarkable resemblances to the synaptic innervation at the MRO: (1) The mechanosensory neurons are accompanied by several fine fibers of central origin, which are presynaptic upon the mechanoreceptors. Efferent control of sensory function has only recently been confirmed electrophysiologically for the peripheral innervation of spider slit sensilla. (2) Different microcircuit configuration types, identified on the basis of the structural organization of their synapses. (3) Synaptic contacts, not only upon the sensory neurons but also between the efferent fibers themselves. (4) Two identified neurotransmitter candidates, GABA and glutamate. Physiological evidence for GABAergic and glutamatergic transmission is incomplete at spider sensilla. Given that the sensory neurons are quite different in their location and origin, these parallels are most likely convergent. Although their significance is only partially understood, mostly from work on the MRO, the close similarities seem to reflect functional constraints on the organization of efferent pathways in the brain and in the periphery. Microsc. Res. Tech. 58:283,298, 2002. © 2002 Wiley-Liss, Inc. [source] Synaptic structure, distribution, and circuitry in the central nervous system of the locust and related insectsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 3 2002Alan Hugh David Watson Abstract The Orthopteran central nervous system has proved a fertile substrate for combined morphological and physiological studies of identified neurons. Electron microscopy reveals two major types of synaptic contacts between nerve fibres: chemical synapses (which predominate) and electrotonic (gap) junctions. The chemical synapses are characterized by a structural asymmetry between the pre- and postsynaptic electron dense paramembranous structures. The postsynaptic paramembranous density defines the extent of a synaptic contact that varies according to synaptic type and location in single identified neurons. Synaptic bars are the most prominent presynaptic element at both monadic and dyadic (divergent) synapses. These are associated with small electron lucent synaptic vesicles in neurons that are cholinergic or glutamatergic (round vesicles) or GABAergic (pleomorphic vesicles). Dense core vesicles of different sizes are indicative of the presence of peptide or amine transmitters. Synapses are mostly found on small-diameter neuropilar branches and the number of synaptic contacts constituting a single physiological synapse ranges from a few tens to several thousand depending on the neurones involved. Some principles of synaptic circuitry can be deduced from the analysis of highly ordered brain neuropiles. With the light microscope, synaptic location can be inferred from the distribution of the presynaptic protein synapsin I. In the ventral nerve cord, identified neurons that are components of circuits subserving known behaviours, have been studied using electrophysiology in combination with light and electron microscopy and immunocytochemistry of neuroactive compounds. This has allowed the synaptic distribution of the major classes of neurone in the ventral nerve cord to be analysed within a functional context. Microsc. Res. Tech. 56:210,226, 2002. © 2002 Wiley-Liss, Inc. [source] Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2006M. J. Lim Autoantibodies to glutamic acid decarboxylase (GAD65) have been reported in sera from the Cln3,/, mouse model of juvenile neuronal ceroid lipofuscinosis (JNCL), and in individuals with this fatal paediatric neurodegenerative disorder. To investigate the existence of other circulating autoreactive antibodies, we used sera from patients with JNCL and other forms of neuronal ceroid lipofuscinosis (NCL) as primary antisera to stain rat and human central nervous system sections. JNCL sera displayed characteristic patterns of IgG, but not IgA, IgE or IgM immunoreactivity that was distinct from the other forms of NCL. Immunoreactivity of JNCL sera was not confined to GAD65-positive (GABAergic) neurons, but also stained multiple other cell populations. Preadsorption of JNCL sera with recombinant GAD65 reduced the intensity of the immunoreactivity, but did not significantly change its staining pattern. Moreover, sera from Stiff Person Syndrome and Type I Diabetes, disorders in which GAD65 autoantibodies are present, stained with profiles that were markedly different from JNCL sera. Collectively, these studies provide evidence of the presence of autoreactive antibodies within multiple forms of NCL, and are not exclusively directed towards GAD65. [source] Visual deprivation increases accumulation of dense core vesicles in developing optic tectal synapses in Xenopus laevisTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 12 2010Jianli Li Abstract Despite considerable progress in understanding the molecular components of synapses in the central nervous system, the ultrastructural rearrangements underlying synaptic development remain unclear. We used serial section transmission electron microscopy and three-dimensional reconstructions of the optic tectal neuropil of Xenopus laevis tadpoles to detect and quantify changes in synaptic ultrastructure over a 1-week period from stages 39 and 47, during which time the visual system of Xenopus tadpoles becomes functional. Synapse density, presynaptic maturation index, and number of synapses per axon bouton increase, whereas the number of DCVs per bouton decreases, between stages 39 and 47. The width of the synaptic cleft decreased and the diameter of postsynaptic profiles increased between stages 39 and 47 and then remained relatively unchanged after stage 47. We found no significant difference in synapse maturation between GABAergic and non-GABAergic synapses. To test the effect of visual experience on synaptogenesis, animals were deprived of visual experience for 3 days from stage 42 to 47. Visual deprivation decreased synapse maturation and the number of connections per bouton. Furthermore, visual deprivation increased the number of DCVs per bouton by more than twofold. The visual-deprivation-induced decrease in synaptic connections is specific to asymmetric non-GABAergic synapses; however, both symmetric GABAergic and asymmetric synapses show comparable increases in the number DCVs with visual deprivation. In both the control and the visually deprived animals, the number of DCVs per bouton is highly variable and does not correlate with either synapse maturation or the number of connected partners per bouton. These data suggest that synaptogenesis and DCV accumulation are regulated by visual experience and further suggest a complex spatial and temporal relation between DCV accumulation and synapse formation. J. Comp. Neurol. 518:2365,2381, 2010. © 2010 Wiley-Liss, Inc. [source] | |||||||||||||