??5 Subunit-containing GABAA receptors form clusters at GABAergic synapses in hippocampal cultures

Christie, Sean B.; Blas, Angel L. De

doi:10.1097/00001756-200212030-00037

Cited by 54 publications

(51 citation statements)

References 14 publications

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“…Although THIP produced a comparable tonic conductance under resting conditions, the tonic conductance may not be equivalent during or after 10 Hz stimulation. Finally, although ␣5GABA A Rs are thought to predominantly generate a "tonic" form of inhibition, high-frequency trains of stimuli may recruit these receptors through spillover of GABA from the synaptic cleft and activation of a limited number of synaptic ␣5GABA A Rs (Christie and de Blas, 2002;Serwanski et al, 2006;Zarnowska et al, 2009). In the mouse hippocampus, ␣5GABA A Rs contribute to a small subset of large-amplitude evoked IPSCs that have been referred to as slow IPSCs (Zarnowska et al, 2009;Vargas-Caballero et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Martin¹,

Zurek²,

MacDonald³

et al. 2010

J. Neurosci.

159

138

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Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABA A R)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABA A R subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by ␣5 subunit-containing GABA A Rs (␣5GABA A Rs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the ␣5 subunit of the GABA A R (Gabra5 ؊/؊ mice). In addition, the strength of fearassociated memory was studied. The results showed that ␣5GABA A R activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10 -20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of ␣5GABA A Rs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by ␣5GABA A Rs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, ␣5GABA A R activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticity in vitro and certain forms of memory in vivo.

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Section: Discussionmentioning

confidence: 99%

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Martin¹,

Zurek²,

MacDonald³

et al. 2010

J. Neurosci.

159

138

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“…HEK 293 cells or rat neuroblastoma B103 cells were cultured on poly-L-lysinecoated 18-mm coverslips, as described elsewhere (25,36). The immunofluorescence procedure has been described elsewhere (24,37). Cultured high density hippocampal neurons (10 DIV), HEK 293 cells, or rat neuroblastoma B103 cells were transfected with 2 g total of various plasmids for protein or shRNA expression using the CalPhos mammalian transfection kit (BD Biosciences), following the instructions of the manufacturer.…”

Section: Subcellular Fractionation Of Rat Brain and Preparation And Fmentioning

confidence: 99%

Septin 11 Is Present in GABAergic Synapses and Plays a Functional Role in the Cytoarchitecture of Neurons and GABAergic Synaptic Connectivity

Serwanski

Miralles

et al. 2009

Journal of Biological Chemistry

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Mass spectrometry and immunoblot analysis of a rat brain fraction enriched in type-II postsynaptic densities and postsynaptic GABAergic markers showed enrichment in the protein septin 11. Septin 11 is expressed throughout the brain, being particularly high in the spiny branchlets of the Purkinje cells in the molecular layer of cerebellum and in the olfactory bulb. Immunofluorescence of cultured hippocampal neurons showed that 54 ؎ 4% of the GABAergic synapses and 25 ؎ 2% of the glutamatergic synapses had colocalizing septin 11 clusters. Similar colocalization numbers were found in the molecular layer of cerebellar sections. In cultured hippocampal neurons, septin 11 clusters were frequently present at the base of dendritic protrusions and at the bifurcation points of the dendritic branches. Electron microscopy immunocytochemistry of the rat brain cerebellum revealed the accumulation of septin 11 at the neck of dendritic spines, at the bifurcation of dendritic branches, and at some GABAergic synapses. Knocking down septin 11 in cultured hippocampal neurons with septin 11 small hairpin RNAs showed (i) reduced dendritic arborization; (ii) decreased density and increased length of dendritic protrusions; and (iii) decreased GABAergic synaptic contacts that these neurons receive. The results indicate that septin 11 plays important roles in the cytoarchitecture of neurons, including dendritic arborization and dendritic spines, and that septin 11 also plays a role in GABAergic synaptic connectivity.We have recently developed a method for the preparation of a brain fraction enriched in GABAergic postsynaptic complex (1). This fraction, insoluble in Triton X-100, was enriched in Gray's type-II postsynaptic densities (type-II PSDs) 2 and in the postsynaptic GABAergic markers GABA A receptors (GABA A Rs) and gephyrin. Here we report that septin 11 is a major component of the type-II PSD fraction. Septins are a family of proteins with GTPase activity that form heterooligomeric filaments and ringlike structures that act as diffusion barriers and scaffolds. Septins are involved in cytokinesis, positioning of the mitotic spindle, cellular morphology, vesicle trafficking, apoptosis, neurodegeneration, and neoplasia (2-5). In mammals, 14 septin genes have been identified. Each septin gene is expressed in several spliced forms. Although most septins are highly expressed in the brain (6), only recently is their role in neuronal function (7-9) and in neuropathology (10 -14) is beginning to be addressed for some septins.Septin 11 is expressed in various tissues, including the brain (15), but little is known about the role of septin 11 in the brain. Septins 3, 5, 6, and 7 are localized in the presynaptic terminals, frequently associated with synaptic vesicles (6,16,17). In neurons, septin 11 forms heterooligomeric complexes with septin 7 and septin 5 (9, 18). Nevertheless, the regional and developmental distribution of septin 11 in the brain and in hippocampal cultures is not identical to that of septin 7 or septin 5 (8). These result...

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“…GABA A receptor density at individual synapses varies in response to plastic changes induced by normal physiological activity (Christie and de Blas, 2002), or pathological conditions. Such plasticity is observed in the rat SNr, after striatal lesions (an animal model of Huntington's disease), which results in an increased density of GABA A receptor subunits at synapses established by degenerating striatonigral terminals (Fujiyama et al, 2002).…”

Section: Gaba a Receptorsmentioning

confidence: 99%

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

2006

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GABA and glutamate, the main transmitters in the basal ganglia, exert their effects through ionotropic and metabotropic receptors. The dynamic activation of these receptors in response to released neurotransmitter depends, among other factors, on their precise localization in relation to corresponding synapses. The use of high resolution quantitative electron microscope immunocytochemical techniques has provided in-depth description of the subcellular and subsynaptic localization of these receptors in the CNS. In this article, we review recent findings on the ultrastructural localization of GABA and glutamate receptors and transporters in the basal ganglia, at synaptic, extrasynaptic and presynaptic sites. The anatomical evidence supports numerous potential locations for receptor-neurotransmitter interactions, and raises important questions regarding mechanisms of activation and function of synaptic versus extrasynaptic receptors in the basal ganglia.

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??5 Subunit-containing GABAA receptors form clusters at GABAergic synapses in hippocampal cultures

Cited by 54 publications

References 14 publications

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Septin 11 Is Present in GABAergic Synapses and Plays a Functional Role in the Cytoarchitecture of Neurons and GABAergic Synaptic Connectivity

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

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??5 Subunit-containing GABAA receptors form clusters at GABAergic synapses in hippocampal cultures

Cited by 54 publications

References 14 publications

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Septin 11 Is Present in GABAergic Synapses and Plays a Functional Role in the Cytoarchitecture of Neurons and GABAergic Synaptic Connectivity

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

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Product

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α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory