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Glutamatergic
Terms modified by Glutamatergic Selected AbstractsGlutamate drives the touch response through a rostral loop in the spinal cord of zebrafish embryosDEVELOPMENTAL NEUROBIOLOGY, Issue 12 2009Thomas Pietri Abstract Characterizing connectivity in the spinal cord of zebrafish embryos is not only prerequisite to understanding the development of locomotion, but is also necessary for maximizing the potential of genetic studies of circuit formation in this model system. During their first day of development, zebrafish embryos show two simple motor behaviors. First, they coil their trunks spontaneously, and a few hours later they start responding to touch with contralateral coils. These behaviors are contemporaneous until spontaneous coils become infrequent by 30 h. Glutamatergic neurons are distributed throughout the embryonic spinal cord, but their contribution to these early motor behaviors in immature zebrafish is still unclear. We demonstrate that the kinetics of spontaneous coiling and touch-evoked responses show distinct developmental time courses and that the touch response is dependent on AMPA-type glutamate receptor activation. Transection experiments suggest that the circuits required for touch-evoked responses are confined to the spinal cord and that only the most rostral part of the spinal cord is sufficient for triggering the full response. This rostral sensory connection is presumably established via CoPA interneurons, as they project to the rostral spinal cord. Electrophysiological analysis demonstrates that these neurons receive short latency AMPA-type glutamatergic inputs in response to ipsilateral tactile stimuli. We conclude that touch responses in early embryonic zebrafish arise only after glutamatergic synapses connect sensory neurons and interneurons to the contralateral motor network via a rostral loop. This helps define an elementary circuit that is modified by the addition of sensory inputs, resulting in behavioral transformation. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2009 [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] Neuronal plasticity: implications in epilepsy progression and managementDRUG DEVELOPMENT RESEARCH, Issue 8 2007Sherifa A. HamedArticle first published online: 12 FEB 200 Abstract Epilepsy is a common neurological disease. A growing number of research studies provide evidence regarding the progressive neuronal damage induced by prolonged seizures or status epilepticus (SE), as well as recurrent brief seizures. Importantly, seizure is only one aspect of epilepsy. However, cognitive and behavioral deficits induced by progressive seizures or antiepileptic treatment can be detrimental to individual function. The neurobiology of epilepsy is poorly understood involving complex cellular and molecular mechanisms. The brain undergoes changes in its basic structure and function, e.g., neural plasticity with an increased susceptibility in neuronal synchronization and network circuit alterations. Some of these changes are transient, while others are permanent with an involvement of both glutamatergic and ,-aminobutyric acid (GABA)ergic systems. Recent data suggest that impaired neuronal plasticity may underlie the cognitive impairment and behavioral changes associated with epilepsy. Many neurologists recognize that the prevention or suppression of seizures by the use of antiepileptic drugs (AEDs) alone is insufficient without clear predictions of disease outcome. Hence, it is important to understand the molecular mechanisms underlying epileptogenesis because this may allow the development of innovative strategies to prevent or cure this condition. In addition, this realization would have significant impact in reducing the long-term adverse consequences of the disease, including neurocognitive and behavioral adverse effects. Drug Dev Res 68:498,511, 2007. © 2008 Wiley-Liss, Inc. [source] Epileptiform synchronization in the cingulate cortexEPILEPSIA, Issue 3 2009Gabriella Panuccio Summary Purpose:, The anterior cingulate cortex (ACC),which plays a role in pain, emotions and behavior,can generate epileptic seizures. To date, little is known on the neuronal mechanisms leading to epileptiform synchronization in this structure. Therefore, we investigated the role of excitatory and inhibitory synaptic transmission in epileptiform activity in this cortical area. In addition, since the ACC presents with a high density of opioid receptors, we studied the effect of opioid agonism on epileptiform synchronization in this brain region. Methods:, We used field and intracellular recordings in conjunction with pharmacological manipulations to characterize the epileptiform activity generated by the rat ACC in a brain slice preparation. Results:, Bath-application of the convulsant 4-aminopyridine (4AP, 50 ,M) induced both brief and prolonged periods of epileptiform synchronization resembling interictal- and ictal-like discharges, respectively. Interictal events could occur more frequently before the onset of ictal activity that was contributed by N -methyl- d -aspartate (NMDA) receptors. Mu-opioid receptor activation abolished 4AP-induced ictal events and markedly reduced the occurrence of the pharmacologically isolated GABAergic synchronous potentials. Ictal discharges were replaced by interictal events during GABAergic antagonism; this GABA-independent activity was influenced by subsequent mu-opioid agonist application. Conclusions:, Our results indicate that both glutamatergic and GABAergic signaling contribute to epileptiform synchronization leading to the generation of electrographic ictal events in the ACC. In addition, mu-opioid receptors appear to modulate both excitatory and inhibitory mechanisms, thus influencing epileptiform synchronization in the ACC. [source] REVIEW: Identifying the neural circuitry of alcohol craving and relapse vulnerabilityADDICTION BIOLOGY, Issue 1 2009Andreas Heinz ABSTRACT With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol-associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options. [source] Roles of light and serotonin in the regulation of gastrin-releasing peptide and arginine vasopressin output in the hamster SCN circadian clockEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2010Jessica M. Francl Abstract Daily timing of the mammalian circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic input from the retina via the retinohypothalamic tract. This signaling is mediated by glutamate, which activates SCN retinorecipient units communicating to pacemaker cells in part through the release of gastrin-releasing peptide (GRP). Efferent signaling from the SCN involves another SCN-containing peptide, arginine vasopressin (AVP). Little is known regarding the mechanisms regulating these peptides, as literature on in vivo peptide release in the SCN is sparse. Here, microdialysis,radioimmunoassay procedures were used to characterize mechanisms controlling GRP and AVP release in the hamster SCN. In animals housed under a 14/10-h light,dark cycle both peptides exhibited daily fluctuations of release, with levels increasing during the morning to peak around midday. Under constant darkness, this pattern persisted for AVP, but rhythmicity was altered for GRP, characterized by a broad plateau throughout the subjective night and early subjective day. Neuronal release of the peptides was confirmed by their suppression with reverse-microdialysis perfusion of calcium blockers and stimulation with depolarizing agents. Reverse-microdialysis perfusion with the 5-HT1A,7 agonist 8-OH-DPAT ((±)-8-hydroxydipropylaminotetralin hydrobromide) during the day significantly suppressed GRP but had little effect on AVP. Also, perfusion with the glutamate agonist NMDA, or exposure to light at night, increased GRP but did not affect AVP. These analyses reveal distinct daily rhythms of SCN peptidergic activity, with GRP but not AVP release attenuated by serotonergic activation that inhibits photic phase-resetting, and activated by glutamatergic and photic stimulation that mediate this phase-resetting. [source] Attention , oscillations and neuropharmacologyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2009Gustavo Deco Abstract Attention is a rich psychological and neurobiological construct that influences almost all aspects of cognitive behaviour. It enables enhanced processing of behaviourally relevant stimuli at the expense of irrelevant stimuli. At the cellular level, rhythmic synchronization at local and long-range spatial scales complements the attention-induced firing rate changes of neurons. The former is hypothesized to enable efficient communication between neuronal ensembles tuned to spatial and featural aspects of the attended stimulus. Recent modelling studies suggest that the rhythmic synchronization in the gamma range may be mediated by a fine balance between N -methyl- d -aspartate and ,-amino-3-hydroxy-5-methylisoxazole-4-propionate postsynaptic currents, whereas other studies have highlighted the possible contribution of the neuromodulator acetylcholine. This review summarizes some recent modelling and experimental studies investigating mechanisms of attention in sensory areas and discusses possibilities of how glutamatergic and cholinergic systems could contribute to increased processing abilities at the cellular and network level during states of top-down attention. [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] Heterogeneity of V2-derived interneurons in the adult mouse spinal cordEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007A. Al-Mosawie Abstract Spinal neurons and networks that generate rhythmic locomotor activity remain incompletely defined, prompting the use of molecular biological strategies to label populations of neurons in the postnatal mouse. During spinal cord development, expression of Lhx3 in the absence of Isl1 specifies a V2 interneuronal fate. In this study, postnatal V2-derived interneurons were identified by yellow fluorescent protein (YFP) expression in the double-transgenic offspring of Lhx3Cre/+ × thy1-loxP-stop-loxP-YFP mice. While some motoneurons were labelled, several populations of interneurons predominantly located in lamina VII could also be distinguished. Small interneurons were located throughout the spinal cord whereas larger interneurons were concentrated in the lumbar enlargement. Some V2-derived interneurons were propriospinal, with axons that bifurcated in the lateral funiculus. V2-derived interneurons gave rise to populations of both excitatory and inhibitory interneurons in approximately equal proportions, as demonstrated by in situ hybridization with VGLUT2 mRNA. Immunohistochemical studies revealed YFP+ boutons throughout the spinal cord. Both glutamatergic and glycinergic YFP+ boutons were observed in lamina IX where many apposed motoneuron somata. GABAergic YFP+ boutons were also observed in lamina IX, and they did not form P-boutons. At P0, more than half of the YFP+ interneurons expressed Chx10 and thus were derived from the V2a subclass. In adult mice, there was an increase in Fos expression in V2-derived interneurons following locomotion, indicating that these neurons are active during this behaviour. The heterogeneity of V2-derived interneurons in adult mice indicates that physiologically distinct subpopulations, including last-order interneurons, arise from these embryonically defined neurons. [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] Selective 5-HT1B receptor inhibition of glutamatergic and GABAergic synaptic activity in the rat dorsal and median rapheEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2006Julia C. Lemos Abstract The dorsal (DR) and median (MR) raphe nuclei contain 5-hydroxytryptamine (5-HT) cell bodies that give rise to the majority of the ascending 5-HT projections to the forebrain. The DR and MR have differential roles in mediating stress, anxiety and depression. Glutamate and GABA activity sculpt putative 5-HT neuronal firing and 5-HT release in a seemingly differential manner in the MR and DR, yet isolated glutamate and GABA activity within the DR and MR has not been systematically characterized. Visualized whole-cell voltage-clamp techniques were used to record excitatory and inhibitory postsynaptic currents (EPSC and IPSC) in 5-HT-containing neurons. There was a regional variation in action potential-dependent (spontaneous) and basal [miniature (m)] glutamate and GABAergic activity. mEPSC activity was greater than mIPSC activity in the DR, whereas in the MR the mIPSC activity was greater. These differences in EPSC and IPSC frequency indicate that glutamatergic and GABAergic input have distinct cytoarchitectures in the DR and MR. 5-HT1B receptor activation decreased mEPSC frequency in the DR and the MR, but selectively inhibited mIPSC activity only in the MR. This finding, in concert with its previously described function as an autoreceptor, suggests that 5-HT1B receptors influence the ascending 5-HT system through multiple mechanisms. The disparity in organization and integration of glutamatergic and GABAergic input to DR and MR neurons and their regulation by 5-HT1B receptors may contribute to the distinction in MR and DR regulation of forebrain regions and their differential function in the aetiology and pharmacological treatment of psychiatric disease states. [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] Bidirectional synaptic plasticity as a consequence of interdependent Ca2+ -controlled phosphorylation and dephosphorylation pathwaysEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2003Pablo D'Alcantara Abstract Postsynaptic Ca2+ signals of different amplitudes and durations are able to induce either long-lasting potentiation (LPT) or depression (LTD). The bidirectional character of synaptic plasticity may result at least in part from an increased or decreased responsiveness of the glutamatergic ,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPA-R) due to the modification of conductance and/or channel number, and controlled by the balance between the activities of phosphorylation and dephosphorylation pathways. AMPA-R depression can be induced by a long-lived Ca2+ signal of moderate amplitude favouring the activation of the dephosphorylation pathway, whereas a shorter but higher Ca2+ signal would induce AMPA-R potentiation resulting from the preferential activation of the phosphorylation pathway. Within the framework of a model involving calcium/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B) and type 1 protein phosphatase (PP1), we aimed at delineating the conditions allowing a biphasic U-shaped relationship between AMPA-R and Ca2+ signal amplitude, and thus bidirectional plasticity. Our theoretical analysis shows that such a property may be observed if the phosphorylation pathway: (i) displays higher cooperativity in its Ca2+ -dependence than the dephosphorylation pathway; (ii) displays a basal Ca2+ -independent activity; or (iii) is directly inhibited by the dephosphorylation pathway. Because the experimentally observed inactivation of CaMKII by PP1 accounts for this latter characteristic, we aimed at verifying whether a realistic model using reported parameters values can simulate the induction of either LTP or LTD, depending on the time and amplitude characteristics of the Ca2+ signal. Our simulations demonstrate that the experimentally observed bidirectional nature of Ca2+ -dependent synaptic plasticity could be the consequence of the PP1-mediated inactivation of CaMKII. [source] Ionic currents underlying rhythmic bursting of ventral mossy cells in the developing mouse dentate gyrusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Shozo Jinno Abstract The electrophysiological properties of mossy cells were examined in developing mouse hippocampal slices using whole-cell patch-clamp techniques, with particular reference to the dorsoventral difference. Dorsal mossy cells exhibited a higher spontaneous excitatory postsynaptic potential (EPSP) frequency and larger maximal EPSP amplitude than ventral mossy cells. On the other hand, the blockade of synaptic inputs with glutamatergic and GABAergic antagonists disclosed a remarkable dorsoventral difference in the intrinsic activity: none (0/27) of the dorsal mossy cells showed intrinsic bursting, whereas the majority (35/47) of the ventral mossy cells exhibited intrinsic rhythmic bursting. To characterize the ionic currents underlying the rhythmic bursting of mossy cells, we used somatic voltage-clamp recordings in the subthreshold voltage range. Ventral bursting cells possessed both hyperpolarization-activated current (Ih) and persistent sodium current (INaP), whereas dorsal and ventral nonbursting cells possessed Ih but no INaP. Blockade of Ih with cesium did not affect the intrinsic bursting of ventral mossy cells. In contrast, the blockade of INaP with tetrodotoxin or phenytoin established a stable subthreshold membrane potential in ventral bursting cells. The current,voltage curve of ventral bursting cells showed a region of tetrodotoxin-sensitive negative slope conductance between ,55 mV and a spike threshold (, ,45 mV). On the other hand, no subthreshold calcium conductances played a significant role in the intrinsic bursting of ventral mossy cells. These observations demonstrate the heterogeneous electrophysiological properties of hilar mossy cells, and suggest that the subthreshold INaP plays a major role in the intrinsic rhythmic bursting of ventral mossy cells. [source] The expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in neurochemically defined axonal populations in the rat spinal cord with emphasis on the dorsal hornEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003A. J. Todd Abstract Two vesicular glutamate transporters, VGLUT1 and VGLUT2, have recently been identified, and it has been reported that they are expressed by largely nonoverlapping populations of glutamatergic neurons in the brain. We have used immunocytochemistry with antibodies against both transporters, together with markers for various populations of spinal neurons, in an attempt to identify glutamatergic interneurons in the dorsal horn of the mid-lumbar spinal cord of the rat. The great majority (94,100%) of nonprimary axonal boutons that contained somatostatin, substance P or neurotensin, as well as 85% of those that contained enkephalin, were VGLUT2-immunoreactive, which suggests that most dorsal horn neurons that synthesize these peptides are glutamatergic. In support of this, we found that most somatostatin- and enkephalin-containing boutons (including somatostatin-immunoreactive boutons that lacked calcitonin gene-related peptide and were therefore probably derived from local interneurons) formed synapses at which AMPA receptors were present. We also investigated VGLUT expression in central terminals of primary afferents. Myelinated afferents were identified with cholera toxin B subunit; most of those in lamina I were VGLUT2-immunoreactive, whereas all those in deeper laminae were VGLUT1-immunoreactive, and some (in laminae III,VI) appeared to contain both transporters. However, peptidergic primary afferents that contained substance P or somatostatin (most of which are unmyelinated), as well as nonpeptidergic C fibres (identified with Bandeiraea simplicifolia isolectin B4) showed low levels of VGLUT2-immunoreactivity, or were not immunoreactive with either VGLUT antibody. As all primary afferents are thought to be glutamatergic, this raises the possibility that unmyelinated afferents, most of which are nociceptors, express a different vesicular glutamate transporter. [source] The effects of the glutamate antagonist memantine on brain activation to an auditory perception taskHUMAN BRAIN MAPPING, Issue 11 2009Heidi van Wageningen Abstract Glutamate is critically involved in the regulation of cognitive functions in humans. There is, however, sparse evidence regarding how blocking glutamate action at the receptor site during a cognitive task affects brain activation. In the current study, the effects of the glutamate antagonist memantine were examined with functional magnetic resonance imaging (fMRI). Thirty-one healthy adults were scanned twice in a counter-balanced design, either in a no-drug session or after administration of memantine for 21 days. The subjects performed a simple auditory perception task with consonant-vowel stimuli. Group-level spatial independent component analysis (ICA) was used to decompose the data and to extract task-related activations. The focus was on four task-related ICA components with frontotemporal localization. The results showed that glutamate-blockage resulted in a significant enhancement in one component, with no significant effect in the other three components. The enhanced effect of memantine was in the middle temporal gyrus, superior frontal gyrus, and middle frontal gyrus. It is suggested that the results reflect effects of glutamatergic processes primarily through non- N -methyl- D -aspartate (NMDA) receptor pathways. Moreover, the results demonstrate that memantine can be used as a probe which allows for studying the effect of excitatory neurotransmission on neuronal activation. Hum Brain Mapp, 2009. © 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] Glutamatergic systems in Alzheimer's diseaseINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue S1 2003Paul T. Francis Abstract Glutamate is the major transmitter of the brain and is involved in all aspects of cognitive function since it is the transmitter of cortical and hippocampal pyramidal neurones. Furthermore, glutamate and glutamate receptors are involved in long-term potentiation, a process believed to underlie learning and memory. Histological studies indicate loss of pyramidal neurones and their synapses in Alzheimer's disease (AD), this together with biochemical evidence suggests presynaptic (and postsynaptic) glutamatergic hypoactivity. This represents a ,double blow' as the activity of glutamatergic neurones is heavily influenced by the cholinergic system, which is also dysfunctional in AD. The clinical relevance of these changes is emphasised because glutamatergic and cholinergic dysfunction are strong correlates of cognitive decline in AD. The mechanism by which glutamatergic (and cholinergic) cells die is likely to be a combination of necrosis and apoptosis caused by a range of factors which include tangle formation and the effects of too much and too little glutamatergic neurotransmission. Copyright © 2003 John Wiley & Sons, Ltd. [source] Intrathecal glutamate promotes glycinergic neuronal activity and inhibits the micturition reflex in urethane-anesthetized ratsINTERNATIONAL JOURNAL OF UROLOGY, Issue 12 2006KATSUHIRO ASHITOMI Objectives: In order to clarify the role of glutamate in the micturition reflex and in glutamatergic and glycinergic neuronal activity, we examined the effects of intrathecal (IT) injection of glutamate or MK-801 (an N- methyl-D-aspartate receptor antagonist) on bladder activity and on the glutamate and glycine levels in the lumbosacral cord of female rats with or without acute lower thoracic spinal cord injury (SCI). Methods: Under urethane anesthesia, isovolumetric cystometry was performed in rats with or without SCI before and after IT injection of glutamate or MK-801 at the lumbosacral cord level. The glutamate and glycine levels of the whole lumbosacral cord were measured after IT injection of glutamate or MK-801 in both groups. Results: In intact rats, IT glutamate (100 µg) prolonged the interval between bladder contractions and decreased the amplitude of contractions. IT MK-801 (3,100 µg) also prolonged the interval between bladder contractions and decreased the amplitude in intact rats. In SCI rats, cystometry demonstrated the disappearance of bladder contractions, and the glycine level in the lumbosacral cord was elevated. In intact rats, IT glutamate (0.3,100 µg) increased the glycine level in the lumbosacral cord. On the other hand, IT MK-801 (3,100 µg) decreased both glutamate and glycine levels in intact and SCI rats. Conclusions: These results suggest that glutamatergic neurons have stimulatory projections to both glutamatergic and glycinergic neurons in the lumbosacral cord, and that glutamatergic neurons inhibit the micturition reflex by stimulating glycinergic neurons. [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] Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cellsJOURNAL OF NEUROCHEMISTRY, Issue 5 2009Nuria Cabello Abstract G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu5 receptors (mGlu5R) and dopamine D2 receptors (D2R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu5R, D2R and adenosine A2A receptor (A2AR). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu5R, D2R and A2AR in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu5R/D2R/A2AR oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some 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] An update on the mechanisms of the psychostimulant effects of caffeineJOURNAL OF NEUROCHEMISTRY, Issue 4 2008Sergi Ferré Abstract There has been a long debate about the predominant involvement of the different adenosine receptor subtypes and the preferential role of pre- versus post-synaptic mechanisms in the psychostimulant effects of the adenosine receptor antagonist caffeine. Both striatal A1 and A2A receptors are involved in the motor-activating and probably reinforcing effects of caffeine, although they play a different role under conditions of acute or chronic caffeine administration. The present review emphasizes the key integrative role of adenosine and adenosine receptor heteromers in the computation of information at the level of the striatal spine module (SSM). This local module is mostly represented by the dendritic spine of the medium spiny neuron with its glutamatergic and dopaminergic synapses and astroglial processes that wrap the glutamatergic synapse. In the SSM, adenosine acts both pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A1 and A2A receptors among themselves and with D1 and D2 receptors, respectively. A critical aspect of the mechanisms of the psychostimulant effects of caffeine is its ability to release the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission by acting on different adenosine receptor heteromers localized in different elements of the SSM. [source] GABAA receptors in aging and Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 4 2007Robert A. Rissman Abstract In this article we present a comprehensive review of relevant research and reports on the GABAA receptor in the aged and Alzheimer's disease (AD) brain. In comparison to glutamatergic and cholinergic systems, the GABAergic system is relatively spared in AD, but the precise mechanisms underlying differential vulnerability are not well understood. Using several methods, investigations demonstrate that despite resistance of the GABAergic system to neurodegeneration, particular subunits of the GABAA receptor are altered with age and AD, which can induce compensatory increases in GABAA receptor subunits within surrounding cells. We conclude that although aging- and disease-related changes in GABAA receptor subunits may be modest, the mechanisms that compensate for these changes may alter the pharmacokinetic and physiological properties of the receptor. It is therefore crucial to understand the subunit composition of individual GABAA receptors in the diseased brain when developing therapeutics that act at these receptors. [source] Regulation of Neurotransmitter Release by Metabotropic Glutamate ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2000Jayne Cartmell Abstract: The G protein-coupled metabotropic glutamate (mGlu) receptors are differentially localized at various synapses throughout the brain. Depending on the receptor subtype, they appear to be localized at presynaptic and/or postsynaptic sites, including glial as well as neuronal elements. The heterogeneous distribution of these receptors on glutamate and nonglutamate neurons/cells thus allows modulation of synaptic transmission by a number of different mechanisms. Electrophysiological studies have demonstrated that the activation of mGlu receptors can modulate the activity of Ca2+ or K+ channels, or interfere with release processes downstream of Ca2+ entry, and consequently regulate neuronal synaptic activity. Such changes evoked by mGlu receptors can ultimately regulate transmitter release at both glutamatergic and nonglutamatergic synapses. Increasing neurochemical evidence has emerged, obtained from in vitro and in vivo studies, showing modulation of the release of a variety of transmitters by mGlu receptors. This review addresses the neurochemical evidence for mGlu receptor-mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides. [source] Electrophysiological Identification of the Functional Presynaptic Nerve Terminals on an Isolated Single Vasopressin Neurone of the Rat Supraoptic NucleusJOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2010T. Ohbuchi Release of arginine vasopressin (AVP) and oxytocin from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is under the control of glutamate-dependent excitation and GABA-dependent inhibition. The possible role of the synaptic terminals attached to SON neurones has been investigated using whole-cell patch-clamp recording in in vitro rat brain slice preparations. Recent evidence has provided new insights into the repercussions of glial environment modifications on the physiology of MNCs at the synaptic level in the SON. In the present study, excitatory glutamatergic and inhibitory GABAergic synaptic inputs were recorded from an isolated single SON neurone cultured for 12 h, using the whole-cell patch clamp technique. Neurones expressed an AVP-enhanced green fluorescent protein (eGFP) fusion gene in MNCs. In addition, native synaptic terminals attached to a dissociated AVP-eGFP neurone were visualised with synaptic vesicle markers. These results suggest that the function of presynaptic nerve terminals may be evaluated directly in a single AVP-eGFP neurone. These preparations would be helpful in future studies aiming to electrophysiologically distinguish between the functions of synaptic terminals and glial modifications in the SON neurones. [source] Zinc signaling through glucocorticoid and glutamate signaling in stressful circumstancesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2010Atsushi Takeda Abstract Humans and animals are constantly exposed to environmental stress. The hypothalamic-pituitary-adrenal (HPA) axis responds to stress, followed by glucocorticoid secretion from the adrenal glands. This response serves to maintain homeostasis in the living body through energy mobilization or to restore it. The brain is an important target for glucocorticoids. The hippocampus participates in the regulation of the HPA axis. Stress activates glutamatergic neurons in the hippocampus, and serious stress induces dyshomeostasis of extracellular glutamate. This dyshomeostasis, which is potentiated by glucocorticoids, modifies cognitive and emotional behavior. On the other hand, zinc is necessary for glucocorticoid signaling and is released from glutamatergic (zincergic) neurons to modulate synaptic glutamate signaling. Stress also induces dyshomeostasis of extracellular zinc, which may be linked to dyshomeostasis of extracellular glutamate. Thus, glucocorticoid signaling might also contribute to dyshomeostasis of extracellular zinc. It is likely that zinc signaling participates in cognitive and emotional behavior through glucocorticoid and glutamate signaling under stressful circumstances. This Mini-Review analyzes the relationship among signals of glucocorticoid, glutamate, and zinc under stressful circumstances to elucidate the significance of the zinc signaling in response to stress. © 2010 Wiley-Liss, Inc. [source] Promoting directional axon growth from neural progenitors grafted into the injured spinal cordJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2010Joseph F. Bonner Abstract Spinal cord injury (SCI) is a devastating condition characterized by disruption of axonal connections, failure of axonal regeneration, and loss of motor and sensory function. The therapeutic promise of neural stem cells has been focused on cell replacement, but many obstacles remain in obtaining neuronal integration following transplantation into the injured CNS. This study investigated the neurotransmitter identity and axonal growth potential of neural progenitors following grafting into adult rats with a dorsal column lesion. We found that using a combination of neuronal and glial restricted progenitors (NRP and GRP) produced graft-derived glutamatergic and GABAergic neurons within the injury site, with minimal axonal extension. Administration of brain-derived neurotrophic factor (BDNF) with the graft promoted modest axonal growth from grafted cells. In contrast, injecting a lentiviral vector expressing BDNF rostral into the injured area generated a neurotrophin gradient and promoted directional growth of axons for up to 9 mm. Animals injected with BDNF lentivirus (at 2.5 and 5.0 mm) showed significantly more axons and significantly longer axons than control animals injected with GFP lentivirus. However, only the 5.0-mm-BDNF group showed a preference for extension in the rostral direction. We concluded that NRP/GRP grafts can be used to produce excitatory and inhibitory neurons, and neurotrophin gradients can guide axonal growth from graft-derived neurons toward putative targets. Together they can serve as a building block for neuronal cell replacement of local circuits and formation of neuronal relays. © 2009 Wiley-Liss, Inc. [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] | |||||||||||||