Gephyrin interacts with the glutamate receptor interacting protein 1 isoforms at GABAergic synapses

Yu, Wendou; Charych, Erik I.; Serwanski, David R.; Li, Rong Wen; Ali, Rashid; Bahr, Ben A.; Blas, Angel L. De

doi:10.1111/j.1471-4159.2008.05311.x

Cited by 20 publications

(17 citation statements)

References 67 publications

(117 reference statements)

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“…Immunofluorescence is blocked by the antigenic peptide. In addition, the clusters show apposition to GABAergic presynaptic glutamate decarboxylase (GAD)-containing terminals (Christie et al, 2002a, 2002b; Christie and De Blas, 2003; Charych et al, 2004a, 2004b; Li et al, 2005a; Serwanski et al, 2006; Li et al, 2007; Yu and De Blas, 2008; Yu et al 2008; Li et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

Synaptic and nonsynaptic localization of protocadherin‐γC5 in the rat brain

Serwanski

Miralles

et al. 2010

J of Comparative Neurology

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It has been proposed that γ-protocadherins (Pcdh-γs) are involved in the establishment of specific patterns of neuronal connectivity. Contrary to the other Pcdh-γs, which are expressed in the embryo, Pcdh-γC5 is expressed postnatally in the brain, coinciding with the peak of synaptogenesis. We have developed an antibody specific for Pcdh-γC5 to study the expression and localization of Pcdh-γC5 in brain. Pcdh-γC5 is highly expressed in the olfactory bulb, corpus striatum, dentate gyrus, CA1 region of the hippocampus, layers I and II of the cerebral cortex, the molecular layer of the cerebellum. Pcdh-γC5 is expressed in both neurons and astrocytes. In hippocampal neuronal cultures, and in the absence of astrocytes, a significant percentage of synapses, more GABAergic than glutamatergic, have associated Pcdh-γC5 clusters. Some GABAergic axons show Pcdh-γC5 in the majority of their synapses. Nevertheless, many Pcdh-γC5 clusters are not associated with synapses. In the brain, a significant number of Pcdh-γC5 clusters are located at contact points between neurons and astrocytes. Electron microscope immunocytochemistry of the rat brain shows that i) Pcdh-γC5 is present in some GABAergic and glutamatergic synapses both pre- and postsynaptically; ii) Pcdh-γC5 is also extrasynaptically localized in membranes and in cytoplasmic organelles of neurons and astrocytes; and iii) that Pcdh-γC5 is also localized in perisynaptic astrocyte processes. The results support the notion that i) Pcdh-γC5 plays a role in synaptic specificity and/or synaptic maturation, and ii) that Pcdh-γC5 is involved in neuron-neuron synaptic interactions and in neuron-astrocyte interactions, including perisynaptic neuron-astrocyte interactions.

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Section: Methodsmentioning

confidence: 99%

Synaptic and nonsynaptic localization of protocadherin‐γC5 in the rat brain

Serwanski

Miralles

et al. 2010

J of Comparative Neurology

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“…GRIP1 binds key proteins that regulate glutamatergic signaling, including liprin-α (28), PICK1 (29), KIF5 (30), and NEEP21 (31), and also uses the same PDZ4-6 to bind the GABA receptor-associated protein, gephyrin (32) (Fig. 1A).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism

Mejı́as¹,

Adamczyk²,

Anggono

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P < 0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n = 480) and matched controls (n = 480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P = 0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.

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“…During development, increased concentration of gephyrin precedes the accumulation of GABA A R at synaptic sites and facilitates the formation and stabilization of inhibitory synapses (Christie et al, 2002; Danglot et al, 2003; Swanwick et al, 2006; Fritschy et al, 2008). Removal of gephyrin by gene targeting or siRNA interference strongly affects GABA A R clustering and reduces inhibitory post-synaptic currents, a reciprocal effect on gephyrin clustering and GABAergic innervations has been observed following elimination of γ2 subunits (Essrich et al, 1998; Kneussel et al, 1999; Li et al, 2005; Yu et al, 2008). GABA A R clustering also occurs in neurons lacking gephyrin, but the clusters formed in these conditions have increased mobility and show less accumulation at inhibitory synapses, which reinforces the notion that gephyrin enhance anchoring of receptors at synaptic sites (Levi et al, 2004; Jacob et al, 2005; Yu et al, 2007).…”

Section: Gabaa Receptors and Its Associated Proteinsmentioning

confidence: 99%

The possible role of GABAA receptors and gephyrin in epileptogenesis

González¹

2013

Front. Cell. Neurosci.

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The term epileptogenesis refers to a dynamic alteration in neuronal excitability that promotes the appearance of spontaneous seizures. Temporal lobe epilepsy, the most common type of acquired epilepsy, often develops after an insult to the brain such as trauma, febrile seizures, encephalitis, or status epilepticus. During the pre-epileptic state (also referred as latent or silent period) there is a plethora of molecular, biochemical, and structural changes that lead to the generation of recurrent spontaneous seizures (or epilepsy). The specific contribution of these alterations to epilepsy development is unclear, but a loss of inhibition has been associated with the increased excitability detected in the latent period. A rapid increase in neuronal hyperexcitability could be due, at least in part, to a decline in the number of physiologically active GABAA receptors (GABAAR). Altered expression of scaffolding proteins involved in the trafficking and anchoring of GABAAR could directly impact the stability of GABAergic synapses and promote a deficiency in inhibitory neurotransmission. Uncovering the molecular mechanisms operating during epileptogenesis and its possible impact on the regulation of GABAAR and scaffolding proteins may offer new targets to prevent the development of epilepsy.

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Gephyrin interacts with the glutamate receptor interacting protein 1 isoforms at GABAergic synapses

Cited by 20 publications

References 67 publications

Synaptic and nonsynaptic localization of protocadherin‐γC5 in the rat brain

Synaptic and nonsynaptic localization of protocadherin‐γC5 in the rat brain

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism

The possible role of GABAA receptors and gephyrin in epileptogenesis

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