AMPAR Auxiliary Protein SHISA6 Facilitates Purkinje Cell Synaptic Excitability and Procedural Memory Formation

Peter, Saša; Urbanus, Bastiaan H A; Klaassen, Remco V.; Wu, Bin; Boele, Henk Jan; Azizi, Sameha; Slotman, Johan A.; Houtsmuller, Adriaan B.; Schonewille, Martijn; Hoebeek, Freek E.; Spijker, Sabine; Smit, August B.; Zeeuw, Chris I. De

doi:10.1016/j.celrep.2020.03.079

Cited by 17 publications

(16 citation statements)

References 52 publications

(76 reference statements)

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“…Notably, Shisa7 (CKAMP59) has emerged as an interesting member of the Shisa family in that unlike other CKAMP counterparts, Shisa7 has a direct role in GABA A R regulation at inhibitory synapses ( Han et al, 2019 ). While other CKAMPs are localized at glutamatergic synapses ( von Engelhardt et al, 2010 ; Klaassen et al, 2016 ; Peter et al, 2020 ), we observed that Shisa7 co-localizes specifically with gephyrin and GABA A Rs in hippocampal neurons ( Han et al, 2019 ) and not at excitatory synapses as reported in an earlier study ( Schmitz et al, 2017 ). Functionally, Shisa7 regulated GABA A R trafficking and inhibitory transmission without affecting excitatory synaptic transmission ( Han et al, 2019 ).…”

Section: Recent Advances In Gaba a R Biologysupporting

confidence: 83%

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

2021

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Diverse populations of GABAA receptors (GABAARs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABAAR signaling underlie the pathophysiology behind neurological and neuropsychiatric disorders such as epilepsy, anxiety, and depression. Pharmacological intervention for these disorders relies on several drug classes that target GABAARs, such as benzodiazepines and more recently neurosteroids. It has been widely demonstrated that subunit composition and receptor stoichiometry impact the biophysical and pharmacological properties of GABAARs. However, current GABAAR-targeting drugs have limited subunit selectivity and produce their therapeutic effects concomitantly with undesired side effects. Therefore, there is still a need to develop more selective GABAAR pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABAARs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABAARs, their use as therapeutics, and some of the pitfalls associated with their adverse side effects. We also discuss recent advances toward understanding the structure, function, and pharmacology of GABAARs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABAARs.

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Section: Recent Advances In Gaba a R Biologysupporting

confidence: 83%

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

2021

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“…Our finding that in the KO model, GC activity patterns promote faster learning than MF inputs only for high levels of MF activity might thus explain the discrepancy between spared locomotion and absence of associative learning in GluA4-KO mice. These results are in line with previous studies, where impairments of MF→GC or PF→PC synapses did not cause locomotion defects but affected motor learning ( Andreescu et al, 2011 ; Galliano et al, 2013 ; Peter et al, 2020 ; Seja et al, 2012 ). Indeed, a small number of active GCs may be sufficient for basic motor performance ( Galliano et al, 2013 ; Schweighofer et al, 2001 ).…”

Section: Discussionsupporting

confidence: 93%

“…Several previous studies investigated PF→PC synaptic function and plasticity in cerebellum-dependent motor learning ( Galliano et al, 2013 ; Grasselli et al, 2020 ; Gutierrez-Castellanos et al, 2017 ; Peter et al, 2020 ; Wada et al, 2007 ). Afferent sensory information to the cerebellar cortex is first processed at the upstream MF→GC synapse ( Billings et al, 2014 ; Cayco-Gajic et al, 2017 ), which may support cerebellar learning.…”

Section: Discussionmentioning

confidence: 99%

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

Kita

Albergaria

Machado

et al. 2021

eLife

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AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

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“…Several previous studies investigated PF→PC synaptic function and plasticity in cerebellum-dependent motor learning (Galliano et al, 2013; Grasselli et al, 2020; Gutierrez-Castellanos et al, 2017; Peter et al, 2020; Wada et al, 2007). Afferent sensory information to the cerebellar cortex is first processed at the upstream MF→GC synapse (Billings et al, 2014; Cayco-Gajic et al, 2017), which may contribute to cerebellar learning.…”

Section: Discussionmentioning

confidence: 99%

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

Kita

Albergaria

Machado

et al. 2020

Preprint

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AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we used electrophysiological, computational and behavioral approaches to demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ∼80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational modeling revealed that GluA4 facilitates pattern separation that is important for associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

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AMPAR Auxiliary Protein SHISA6 Facilitates Purkinje Cell Synaptic Excitability and Procedural Memory Formation

Cited by 17 publications

References 52 publications

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

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