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Neural Plasticity (neural + plasticity)

Distribution by Scientific Domains

Life Sciences	78%
Medical Sciences	8%

Distribution within Life Sciences

Neuroscience	83%
Anatomy & Physiology	16%

Selected Abstracts

Peer Commmentaries on Neural plasticity and human development: the role of early experience in sculpting memory systems By Charles A. Nelson

DEVELOPMENTAL SCIENCE, Issue 2 2000
Article first published online: 28 JUN 200
Olivier Pascalis and Michelle de Haan, Subcortical lesion-cortical lesion: what about the hippocampus?, p. 131 J. Steven Reznick, Biology versus experience: balancing the equation, p. 133 [source]

Neural plasticity and human development: the role of early experience in sculpting memory systems

DEVELOPMENTAL SCIENCE, Issue 2 2000
Charles A. Nelson
The concept of sensitive or critical periods in the context of memory development is examined in this paper. I begin by providing examples of the role of experience in influencing sensory, linguistic and emotional functioning. This is followed by a discussion of the role of experience in influencing cognitive functioning, particularly memory. Based on this discussion, speculation is offered that the infant's proclivity for novelty, which makes its appearance shortly after birth, provides critical input into a nervous system that will eventually be set up to learn and remember for the entire lifespan. Because learning and memory are fundamental to the survival of our species, those aspects of the nervous system that permit the encoding and retention of new information are remarkably malleable from the outset, even in the face of some types of neural trauma. This flexibility is retained for many years so long as the learning and memory ,system' is challenged. The implications of this model are discussed in the context of those life events that might undermine the longevity of memory systems. [source]

Neural plasticity and addiction: integrin-linked kinase and cocaine behavioral sensitization

JOURNAL OF NEUROCHEMISTRY, Issue 3 2008
Qiang Chen
Abstract Behavioral sensitization of psychostimulants was accompanied by alterations in a variety of biochemical molecules in different brain regions. However, which change is actually related to drug-produced sensitization lacks of accurate clarification. In this study, we investigated the role of integrin-linked kinase (ILK) in both the induction and expression of cocaine sensitization. Conditional inhibition of ILK expression was established in the nucleus accumbens (NAc) core by microinjecting recombinant adeno-associated virus-carrying, tetracycline-on-regulated small interfering RNA which reversed the chronic cocaine-induced psychomotor sensitization, as well as the changes in protein kinase B Ser473 phosphorylation, dendritic density, and dendritic spine numbers locally. Importantly, the reversed psychomotor sensitization did not recover after cessation of the silencing for 8 days. We also demonstrated that inhibition of ILK expression pre- and during-chronic cocaine treatments blocked the induction of cocaine psychomotor sensitization and abolished the stimulant effect of cocaine on ILK expression. In contrast, inhibition of ILK expression in the NAc core has no significant effect on cocaine-induced stereotypical behaviors. This concludes that ILK is involved in cocaine sensitization with the earlier induction and later expression functioning as a kinase to regulate protein kinase B Ser473 phosphorylation and a scaffolding protein to regulate the reorganization of the NAc spine morphology. [source]

Neural plasticity of neonatal hypoglossal nerve for effective suckling

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2007
Nanae Fukushima
Abstract The adaptive movement of the tongue after unilateral lesion of the hypoglossal (XII) nerve during the early postnatal days is essential for recovery of milk intake. The present study investigated the basic mechanisms underlying such adaptation, focusing on the neural plasticity that allows effective suckling. After resection of the ipsilateral XII nerve on P1, 1,1,-dioctadecyl-3,3,3,,3,-tetramethylindocarbocyanine perchlolate (DiI), a postmortem neuronal tracer, was applied to the contralateral uninjured XII nerve on P4 and P7. DiI-labeled fibers were traced successfully within the tongue and showed gradually increased extension over the XII nerve-injured side in the central core portion of the denervated tongue between P4 and P7. Systematic neuroanatomic experiments showed that contralateral axonal sprouting occurred as early as 1 day after nerve injury (P2), and that such axonal sprouting occurred exclusively from the medial branch of the XII nerve responsible for tongue protrusion, an essential movement for suckling. These findings provide direct evidence of functional neural plasticity that allows effective suckling in XII nerve-injured newborns with suckling disturbance. © 2007 Wiley-Liss, Inc. [source]

Conservation and expression of IQ-domain-containing calpacitin gene products (neuromodulin/GAP-43, neurogranin/RC3) in the adult and developing oscine song control system

DEVELOPMENTAL NEUROBIOLOGY, Issue 2-3 2009
David F. Clayton
Abstract Songbirds are appreciated for the insights they provide into regulated neural plasticity. Here, we describe the comparative analysis and brain expression of two gene sequences encoding probable regulators of synaptic plasticity in songbirds: neuromodulin (GAP-43) and neurogranin (RC3). Both are members of the calpacitin family and share a distinctive conserved core domain that mediates interactions between calcium, calmodulin, and protein kinase C signaling pathways. Comparative sequence analysis is consistent with known phylogenetic relationships, with songbirds most closely related to chicken and progressively more distant from mammals and fish. The C-terminus of neurogranin is different in birds and mammals, and antibodies to the protein reveal high expression in adult zebra finches in cerebellar Purkinje cells, which has not been observed in other species. RNAs for both proteins are generally abundant in the telencephalon yet markedly reduced in certain nuclei of the song control system in adult canaries and zebra finches: neuromodulin RNA is very low in RA and HVC (relative to the surrounding pallial areas), whereas neurogranin RNA is conspicuously low in Area X (relative to surrounding striatum). In both cases, this selective downregulation develops in the zebra finch during the juvenile song learning period, 25,45 days after hatching. These results suggest molecular parallels to the robust stability of the adult avian song control circuit. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source]

Neuronal plasticity: implications in epilepsy progression and management

DRUG DEVELOPMENT RESEARCH, Issue 8 2007
Sherifa 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]

Developmental neural plasticity and its cognitive benefits: olivocerebellar reinnervation compensates for spatial function in the cerebellum

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007
Melina L. Willson
Abstract The adult mammalian central nervous system displays limited reinnervation and recovery from trauma. However, during development, post-lesion plasticity may generate alternative paths, thus providing models to investigate reinnervation and repair. After unilateral transection of the neonatal rat olivocerebellar path (pedunculotomy), axons from the remaining inferior olive reinnervate the denervated hemicerebellum. Unfortunately, reinnervation to the cerebellar hemisphere is incomplete; therefore, its capacity to mediate hemispheric function (navigation) is unknown. We studied sensorimotor control and spatial cognition of rats with and without transcommissural reinnervation using simple (bridge and ladder) and complex (wire) locomotion tests and the Morris water maze (hidden, probe and cued paradigms). Although pedunculotomized animals completed locomotory tasks more slowly than controls, all groups performed equally in the cued maze, indicating that lesioned animals could orientate to and reach the platform. In animals pedunculotomized on day 3 (Px3), which develop olivocerebellar reinnervation, final spatial knowledge was as good as controls, although they learned more erratically, failing to retain all information from one day to the next. By contrast, animals pedunculotomized on day 11 (Px11), which do not develop reinnervation, did not learn the task, taking less direct routes and more time to reach the platform than controls. In the probe test, control and Px3, but not Px11, animals swam directly to the remembered location. Furthermore, the amount of transcommissural reinnervation to the denervated hemisphere correlated directly with spatial performance. These results show that transcommissural olivocerebellar reinnervation is associated with spatial learning, i.e. even partial circuit repair confers significant functional benefit. [source]

Short-term plasticity visualized with flavoprotein autofluorescence in the somatosensory cortex of anaesthetized rats

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2004
Hiroatsu Murakami
Abstract In the present study, short-term plasticity of somatosensory neural responses was investigated using flavoprotein autofluorescence imaging in rats anaesthetized with urethane (1.5 g/kg, i.p.) Somatosensory neural activity was elicited by vibratory skin stimulation (50 Hz for 1 s) applied on the surface of the left plantar hindpaw. Changes in green autofluorescence (, = 500,550 nm) in blue light (, = 450,490 nm) were elicited in the right somatosensory cortex. The normalised maximal fluorescence responses (,F/F) was 2.0 ± 0.1% (n = 40). After tetanic cortical stimulation (TS), applied at a depth of 1.5,2.0 mm from the cortical surface, the responses elicited by peripheral stimulation were significantly potentiated in both peak amplitude and size of the responsive area (both P < 0.02; Wilcoxon signed rank test). This potentiation was clearly observed in the recording session started 5 min after the cessation of TS, and returned to the control level within 30 min. However, depression of the responses was observed after TS applied at a depth of 0.5 mm. TS-induced changes in supragranular field potentials in cortical slices showed a similar dependence on the depth of the stimulated sites. When TS was applied on the ipsilateral somatosensory cortex, marked potentiation of the ipsilateral responses and slight potentiation of the contralateral responses to peripheral stimulation were observed after TS, suggesting the involvement of commissural fibers in the changes in the somatosensory brain maps. The present study clearly demonstrates that functional brain imaging using flavoprotein autofluorescence is a useful technique for investigating neural plasticity in vivo. [source]

Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREB

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2002
Jennifer R. Chao
Abstract Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated specifically via the canonical CRE site. Gel shift assays confirmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity. [source]

Adolescent stress and neural plasticity in hamsters: a vasopressin-serotonin model of inappropriate aggressive behaviour

EXPERIMENTAL PHYSIOLOGY, Issue 2000
Craig F. Ferris
Animal studies show that arginine vasopressin facilitates aggression, while serotonin (5-HT) inhibits aggression by blocking the activity of the vasopressin system. Clinical studies report that subjects with a history of ,fighting and assault' show a significant positive correlation between cerebrospinal fluid concentrations of vasopressin and aggression in the presence of a hyporeactive 5-HT system. Thus, in animals and humans, a hyporeactive 5-HT system may result in enhanced vasopressin activity and increased aggression. Can the stress of emotional and physical insult, i.e. threat and attack, during adolescence affect the development of the vasopressin and 5-HT systems and alter normal aggressive behaviour in early adulthood? Adolescent male golden hamsters were weaned at postnatal day 25, and stressed for 2 weeks by daily 1 h bouts of threat and attack by adult hamsters. Male littermates were run in a parallel stress study using daily 1 h trials of isolation in a novel environment. During early adulthood, on postnatal day 45, 3 days after the cessation of stress trials, animals were tested for aggression in a resident: intruder model. The results show a context-dependent change in aggression. Animals with a history of abuse show exaggerated attack behaviour toward smaller males compared to littermates with a history of isolation stress. Conversely, when confronted by males of equal size, animals with a history of abuse show diminished aggression and increased submission compared to controls. It was determined that the density of vasopressin fibres and neurones in the hypothalamus is lower in abused animals compared to controls. In contrast, the number of 5-HT terminals within the hypothalamus is higher in abused animals compared to controls. These results provide evidence in an animal model that stress in the form of threat and attack during adolescence can alter the balance between vasopressin and 5-HT in the brain, resulting in inappropriate aggressive behaviour in early adulthood. [source]

Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology

GENES, BRAIN AND BEHAVIOR, Issue 3 2009
D. Leo
Methylphenidate (MPH) administration to adolescent rodents produces persistent region-specific changes in brain reward circuits and alterations of reward-based behavior. We show that these modifications include a marked increment of serotonin (5-hydroxy-tryptamine) receptor type 7 (Htr7) expression and synaptic contacts, mainly in the nucleus accumbens, and a reduction of basal behavioral impulsivity. We show that neural and behavioral consequences are functionally related: administration of a selective Htr7 antagonist fully counteracts the MPH-reduced impulsive behavior and enhances impulsivity when administered alone in naive rats. Agonist-induced activation of endogenous Htr7 significantly increases neurite length in striatal neuron primary cultures, thus suggesting plastic remodeling of neuronal morphology. The mixed Htr (1a/7) agonist, 8-OH-DPAT, reduces impulsive behavior in adolescent rats and in naive adults, whose impulsivity is enhanced by the Htr7 antagonist. In summary, behavioral pharmacology experiments show that Htr7 mediates self-control behavior, and brain primary cultures experiments indicate that this receptor may be involved in the underlying neural plasticity, through changes in neuronal cytoarchitecture. [source]

RhoA, encoding a Rho GTPase, is associated with smoking initiation

GENES, BRAIN AND BEHAVIOR, Issue 8 2007
X. Chen
We used microarray analysis of acute nicotine responses in mouse brain to choose rationale candidates for human association studies on tobacco smoking and nicotine dependence (ND). Microarray studies on the time,course of acute response to nicotine in mouse brain identified 95 genes regulated in ventral tegmental area. Among these, 30 genes were part of a gene network, with functions relevant to neural plasticity. On this basis and their known roles in drug abuse or synaptic plasticity, we chose the genes RhoA and Ywhag as candidates for human association studies. A synteny search identified human orthologs and we investigated their role in tobacco smoking and ND in a human case,control association study. We genotyped five and three single nucleotide polymorphisms from the RhoA and Ywhag genes, respectively. Both single marker and haplotype analyses were negative for the Ywhag gene. For the RhoA gene, rs2878298 showed highly significant genotypic association with both smoking initiation (SI) and ND (P = 0.00005 for SI and P = 0.0007 for ND). In the allelic analyses, rs2878298 was only significant for SI. In the multimarker haplotype analyses, significant association with SI was found for the RhoA gene (empirical global P values ranged from 9 × 10,5 to 10,5). In all multimarker combinations analyzed, with or without inclusion of the single most significant marker rs2878298, identical risk and protective haplotypes were identified. Our results indicated that the RhoA gene is likely involved in initiation of tobacco smoking and ND. Replication and future model system studies will be needed to validate the role of RhoA gene in SI and ND. [source]

Abnormal post-translational and extracellular processing of brevican in plaque-bearing mice over-expressing APPsw

JOURNAL OF NEUROCHEMISTRY, Issue 3 2010
Joanne M. Ajmo
J. Neurochem. (2010) 113, 784,795. Abstract Aggregation of amyloid-, (A,) in the forebrain of Alzheimer's disease (AD) subjects may disturb the molecular organization of the extracellular microenvironment that modulates neural and synaptic plasticity. Proteoglycans are major components of this extracellular environment. To test the hypothesis that A,, or another amyloid precursor protein (APP) dependent mechanism modifies the accumulation and/or turnover of extracellular proteoglycans, we examined whether the expression and processing of brevican, an abundant extracellular, chondroitin sulfate (CS)-bearing proteoglycan, were altered in brains of A,-depositing transgenic mice (APPsw , APP gene bearing the Swedish mutation) as a model of AD. The molecular size of CS chains attached to brevican was smaller in hippocampal tissue from APPsw mice bearing A, deposits compared to non-transgenic mice, likely because of changes in the CS chains. Also, the abundance of the major proteolytic fragment of brevican was markedly diminished in extracts from several telencephalic regions of APPsw mice compared to non-transgenic mice, yet these immunoreactive fragments appeared to accumulate adjacent to the plaque edge. These results suggest that A, or APP exert inhibitory effects on proteolytic cleavage mechanisms responsible for synthesis and turnover of proteoglycans. As proteoglycans stabilize synaptic structure and inhibit molecular plasticity, defective brevican processing observed in A,-bearing mice and potentially end-stage human AD, may contribute to deficient neural plasticity. [source]

Reproduction-Induced Neuroplasticity: Natural Behavioural and Neuronal Alterations Associated with the Production and Care of Offspring

JOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2008
Craig H. Kinsley
As a female transitions into motherhood, many neurobiological adaptations are required to meet the demands presented by her offspring. In addition to the traditional maternal responses (e.g. crouching, nursing, retrieving, grooming), our laboratories have observed several behavioural modifications accompanying parity, especially in the areas of foraging and emotional resilience. Additionally, brain modifications have been observed in the hippocampus and amygdala, providing support for neural plasticity extending beyond the expected hypothalamic alterations. Interestingly, we have observed parenting-induced neuroplasticity to persist into late adulthood, even providing protection against age-related brain and memory deficits. Although the majority of work on the parental brain has been conducted on females, preliminary research suggests similar changes in the biparental male California deer mouse. Taken together, research suggests that the parental brain is dynamic and changeable as it undergoes diverse and, in some cases, long-lasting, modifications to facilitate the production and care of offspring. [source]

Yin yang 1 directly regulates the transcription of RE-1 silencing transcription factor

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2008
Lichun Jiang
Abstract The RE-1 silencing transcription factor (REST) is a master transcription factor that plays a critical role in embryo development, especially during the process of neurogenesis and neural plasticity. However, the mechanism of REST gene transcription regulation is still an open question. Here, by combining bioinformatics analysis and experimental studies, we report that the transcription factor Yin Yang 1 (YY1) bound to a conserved YY1 binding site in the promoter of the mouse REST gene and positively regulated activity of this promoter in SH-SY5Y cells. Furthermore, analysis of microarray data revealed a significant correlation between the expression of YY1 and REST genes. Overall, this study suggests that YY1 directly regulates expression of the REST gene. © 2007 Wiley-Liss, Inc. [source]

Neural plasticity of neonatal hypoglossal nerve for effective suckling

Proteomic changes in the crucian carp brain during exposure to anoxia

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 8 2009
Richard W. Smith Dr.
Abstract During exposure to anoxia, the crucian carp brain is able to maintain normal overall protein synthesis rates. However, it is not known if there are alterations in the synthesis or expression of specific proteins. This investigation addresses this issue by comparing the normoxic and anoxic brain proteome. Nine proteins were found to be reduced by anoxia. Reductions in the glycolytic pathway proteins creatine kinase, fructose biphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase and lactate dehydrogenase reflect the reduced production and requirement for adenosine tri-phosphate during anoxia. In terms of neural protection, voltage-dependent anion channel, a protein associated with neuronal apoptosis, was reduced, along with gefiltin, a protein associated with the subsequent need for neuronal repair. Additionally the expression of proteins associated with neural degeneration and impaired cognitive function also declined; dihydropyrimidinase-like protein-3 and vesicle amine transport protein-1. One protein was found to be increased by anoxia; pre-proependymin, the precursor to ependymin. Ependymin fulfils multiple roles in neural plasticity, memory formation and learning, neuron growth and regeneration, and is able to reverse the possibility of apoptosis, thus further protecting the anoxic brain. [source]

Three-dimensional distribution of no sources in a primary mechanosensory integration center in the locust and its implications for volume signaling

THE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 15 2010
Daniel Münch
Abstract Nitric oxide (NO) is an evolutionarily conserved mediator of neural plasticity. Because NO is highly diffusible, signals from multiple sources might combine in space and time to affect the same target. Whether such cooperative effects occur will depend on the effective signaling range and on the distances of NO sources to one another and to their targets. These anatomical parameters have been quantified in only few systems. We analyzed the 3D architecture of NO synthase (NOS) expression in a sensory neuropil, the ventral association center (VAC) of the locust. High-resolution confocal microscopy revealed NOS immunoreactive fiber boutons in submicrometer proximity to both the axon terminals of sensory neurons and their postsynaptic target, interneuron A4I1. Pharmacological manipulation of NO signaling affected the response of A4I1 to individual wind-puff stimuli and the response decrement during repetitive stimulation. Mapping NOS immunoreactivity in defined volumes around dendrites of A4I1 revealed NOS-positive fiber boutons within 5 ,m of nearly every surface point. The mean distances between neighboring NOS-boutons and between any point within the VAC and its nearest NOS-bouton were likewise about 5 ,m. For an NO signal to convey the identity of its source, the effective signaling range would therefore have to be less than 5 ,m, and shorter still when multiple boutons release NO simultaneously. The architecture is therefore well suited to support the cooperative generation of volume signals by interaction between the signals from multiple active boutons. J. Comp. Neurol. 518:2903,2916, 2010. © 2010 Wiley-Liss, Inc. [source]

Three-dimensional distribution of NO sources in a primary mechanosensory integration center in the locust and its implications for volume signaling

Human motor associative plasticity induced by paired bihemispheric stimulation

THE JOURNAL OF PHYSIOLOGY, Issue 19 2009
Satoko Koganemaru
Paired associative stimulation (PAS) is an effective non-invasive method to induce human motor plasticity by the repetitive pairing of peripheral nerve stimulation and transcranial magnetic stimulation (TMS) at the primary motor cortex (M1) with a specific time interval. Although the repetitive pairing of two types of afferent stimulation might be a biological basis of neural plasticity and memory, other types of paired stimulation of the human brain have rarely been studied. We hypothesized that the repetitive pairing of TMS and interhemispheric cortico-cortical projection or paired bihemispheric stimulation (PBS), in which the right and left M1 were serially stimulated with a time interval of 15 ms, would produce an associative long-term potentiation (LTP)-like effect. In this study, 23 right-handed healthy volunteers were subjected to a 0.1 Hz repetition of 180 pairings of bihemispheric TMS, and physiological and behavioural measures of the motor system were compared before, immediately after, 20 min after and 40 min after PBS intervention. The amplitude of the motor evoked potential (MEP) induced by the left M1 stimulation and its input,output function increased for up to ,20 min post-PBS. Fine finger movements were also facilitated by PBS. Spinal excitability measured by the H-reflex was insensitive to PBS, suggesting a cortical mechanism. The associative LTP-like effect induced by PBS was timing dependent, occurring only when the interstimulus interval was 5,25 ms. These findings demonstrate that using PBS in PAS can induce motor cortical plasticity, and this approach might be applicable to the rehabilitation of patients with motor disorders. [source]

Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures

THE JOURNAL OF PHYSIOLOGY, Issue 2 2006
Jin-shun Qi
Deficits in GABAergic inhibitory transmission are a hallmark of temporal lobe epilepsy and have been replicated in animal and tissue culture models of epilepsy. GABAergic inhibition comprises phasic and tonic inhibition that is mediated by synaptic and extrasynaptic GABAA receptors, respectively. We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo. Here, we report a downregulation of tonic GABA inhibition after chronic epileptogenic stimulation of rat hippocampal cultures. Chronic pretreatment of hippocampal neurons with CTZ or KA resulted in a marked reduction in GABAergic inhibition, as shown by a significant decrease in whole-cell GABA currents and in the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Interestingly, synaptically localized GABAA receptors remained relatively stable, as evidenced by the unaltered amplitude of mIPSCs, as well as the unchanged punctate immunoreactivity of ,2 subunit-containing postsynaptic GABAA receptors. In contrast, tonic GABA currents, assessed either by a GABAA receptor antagonist bicuculline or a selective extrasynaptic GABAA receptor agonist THIP, were significantly reduced following epileptogenic stimulation. These results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GABAA receptors unchanged. Thus, in addition to synaptic alteration of GABAergic transmission, regulation of tonic inhibition may also play an important role during epileptogenesis. [source]