1. The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.
- Author
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Nakamura T, Sakaue F, Nasu-Nishimura Y, Takeda Y, Matsuura K, and Akiyama T
- Subjects
- Amygdala physiology, Animals, Autistic Disorder, Cells, Cultured, Fear physiology, Hippocampus cytology, Learning physiology, Male, Mice, Inbred C57BL, Mice, Mutant Strains, gamma-Aminobutyric Acid physiology, GTPase-Activating Proteins physiology, Neuronal Plasticity physiology, Neurons physiology, Receptors, GABA-A physiology
- Abstract
GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)-dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABA
A Rs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABAA R transport driven during NMDAR-dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABAA Rs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS-deficient neurons. This increase in surface GABAA Rs required the PX-RICS/GABARAP/14-3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII-dependent phosphorylation of PX-RICS to promote PX-RICS-14-3-3 assembly. Notably, PX-RICS/RICS-deficient mice showed impaired amygdala-dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS-mediated GABAA R trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2018
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