Distribution of postsynaptic GABA<sub>a</sub> receptor aggregates in the deep cerebellar nuclei of normal and mutant mice

Garin, Nathalie; Hornung, Jean‐Pierre; Escher, Gérard

doi:10.1002/cne.10226

Cited by 24 publications

(15 citation statements)

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“…For example, the effects of GABAergic denervation on GABA A receptor and gephyrin clusters has been investigated in vivo in two lines of mutant mice undergoing postnatal degeneration of Purkinje cells (Lurcher mice and Purkinjecell-degeneration mice) [48]. While the initial formation of GABAergic synapses and gephyrin and GABA A receptor clusters was normal in both lines of mice, the degeneration of Purkinje cells induced a loss of gephyrin clusters in the denervated synapses.…”

Section: Contribution Of Presynaptic Mechanisms: 'Matched' and 'Mismamentioning

confidence: 99%

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Fritschy

Schweizer

Brünig

et al. 2003

Biochemical Society Transactions

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Postsynaptic clustering of GABAA (type A gamma-aminobutyric acid) receptors is essential to ensure proper function of GABAergic synapses. This process is initiated during synapse formation and is maintained throughout life. The tubulin-associated protein gephyrin is required for clustering of GABAA receptors, but its specific role in this process is not understood. A second protein associated selectively with GABAA receptors at postsynaptic sites is dystrophin. It is present in a subset of GABAergic synapses along with several partners, forming the dystrophin-associated protein complex. In this review, we discuss recent advances in the role of neuronal activity and trans-synaptic signaling for the clustering of gephyrin and dystrophin during synaptogenesis and on the role of these proteins for plasticity and maintenance of mature synapses.

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Section: Contribution Of Presynaptic Mechanisms: 'Matched' and 'Mismamentioning

confidence: 99%

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Fritschy

Schweizer

Brünig

et al. 2003

Biochemical Society Transactions

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“…In pcd mice, a spontaneous mutant strain with progressive Purkinje cell degeneration, postsynaptic GABA receptors were found to be upregulated in the DCN to counteract the failing inhibitory input (Garin et al, 2002).…”

Section: Motor Learning and Coordination Impairment In Mice Overexprementioning

confidence: 99%

Synaptic destabilization by neuronal Nogo-A

et al. 2007

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Formation and maintenance of a neuronal network is based on a balance between plasticity and stability of synaptic connections. Several molecules have been found to regulate the maintenance of excitatory synapses but nothing is known about the molecular mechanisms involved in synaptic stabilization versus disassembly at inhibitory synapses. Here, we demonstrate that Nogo-A, which is well known to be present in myelin and inhibit growth in the adult CNS, is present in inhibitory presynaptic terminals in cerebellar Purkinje cells at the time of Purkinje cell-Deep Cerebellar Nuclei (DCN) inhibitory synapse formation and is then downregulated during synapse maturation. We addressed the role of neuronal Nogo-A in synapse maturation by generating several mouse lines overexpressing Nogo-A, starting at postnatal ages and throughout adult life, specifically in cerebellar Purkinje cells and their terminals. The overexpression of Nogo-A induced a progressive disassembly, retraction and loss of the inhibitory Purkinje cell terminals. This led to deficits in motor learning and coordination in the transgenic mice. Prior to synapse disassembly, the overexpression of neuronal Nogo-A led to the downregulation of the synaptic scaffold proteins spectrin, spectrin-E and beta-catenin in the postsynaptic neurons. Our data suggest that neuronal Nogo-A might play a role in the maintenance of inhibitory synapses by modulating the expression of synaptic anchoring molecules.

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“…Complex spikes, and the pauses that follow, are poised to have a greater impact on the DCN, for they involve sudden changes in input. Because inhibitory drive onto the glutamatergic neurons of the DCN undergoes compensatory upregulation in mutant mice lacking Purkinje cells (Garin et al, 2002;Linnemann et al, 2004), it may be possible that DCN neurons can adapt to altered tonic inhibition, whereas there is no evidence that these neurons can adapt to altered temporal summation of burst input with a decelerated intraburst frequency comprised of fewer spikes. These properties suggest that the complex spike alterations reported here are liable to have especially pronounced behavioral ramifications and be less subject to adaptation or compensation in the Kcnc3-null mutant.…”

Section: Perturbed Complex Spikes: Potential Impact On Deep Nuclear Nmentioning

confidence: 99%

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

Hurlock

McMahon²,

Joho³

2008

J. Neurosci.

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The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.Key words: K channels; burst firing; motor dysfunction; cerebellum; Purkinje cell; complex spike IntroductionVoltage-gated potassium (Kv) channels of the Kv3 subfamily enable neurons to fire narrow action potentials at high frequencies beyond ϳ200 Hz. Four separate genes (Kcnc1-Kcnc4 ) encoding subunits Kv3.1-Kv3.4 are expressed in various combinations in CNS neurons in which they assemble into homotetrameric and heterotetrameric channels. Mice lacking the Kcnc3-encoded Kv3.3 subunit exhibit motor deficits manifested as increased lateral deviation while ambulating and increased slips while traversing a narrow beam (McMahon et al., 2004;Joho et al., 2006b). A role for Kv3.3 channels in motor coordination is also underscored by the recent finding that dominant-negative mutations found in the human KCNC3 gene correlate with the neurological disorder spinocerebellar ataxia 13 (Waters et al., 2006). Kv3-type channels are distinguished by exceptionally rapid kinetics of activation and deactivation, rendering them ideally suited to drive repolarization that is rapid, both in its onset and relief, so that the next action potential upstroke can occur with minimal delay in the absence of lingering afterhyperpolarization. High-frequency spiking is facilitated by both minimizing sodium channel inactivation through brief action potentials and by promoting sodium channel deinactivation through the excursion to negative potentials during the fast afterhyperpolarization. Indeed, the loss of Kv3-type channels results in broadened spikes accompanied by decelerated firing (Rudy and McBain, 2001). Unlike most other neuron types in which Kv3.3 subunits are expressed with other Kv3-type subunits, Purkinje cells express high levels of Kv3.3 and lower levels of Kv3.4 (Weiser et al., 1994;Martina et al., 2003). Loss of Kv3.3 results in a doubling of action potential duration (McMahon et al., 2004). Furthermore, blockade with tetraethylammonium (TEA) or BDS-I at a conc...

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Distribution of postsynaptic GABA_a receptor aggregates in the deep cerebellar nuclei of normal and mutant mice

Cited by 24 publications

References 28 publications

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Synaptic destabilization by neuronal Nogo-A

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

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Distribution of postsynaptic GABAa receptor aggregates in the deep cerebellar nuclei of normal and mutant mice

Cited by 24 publications

References 28 publications

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Synaptic destabilization by neuronal Nogo-A

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

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Distribution of postsynaptic GABA_a receptor aggregates in the deep cerebellar nuclei of normal and mutant mice