Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

Murat Kilinc, Thomas K. Creson, Camilo Rojas, Sabyasachi Maity, Aliza A. Le, Julie Lauterborn, Brent Wilkinson, Nicolas Hartel, Nicholas Graham, Adrian Reich, Gemma Gou, Yoichi Araki, Àlex Bayés, Marcelo P. Coba, Gary Lynch, Courtney A. Miller, Gavin Rumbaugh

Research output: Contribution to journalArticlepeer-review

Abstract

SynGAP-α1 is a splice variant of the neurodevelopmental disorder risk gene, SYNGAP1/Syngap1. α1 encodes the C-terminal PDZ binding motif (PBM) that promotes liquid-liquid phase separation, a candidate process for postsynaptic density organization within excitatory synapses. However, it remains unknown how the endogenous SynGAP PBM regulates synapse properties and related cognitive functions. We found that a major PBM function in mice is to limit the mobility of SynGAP-α1 in response to NMDA receptor activation. Genetic disruption of the PBM increased SynGAP-α1 mobility to levels consistent with other non-PBM-containing C-terminal isoforms. This resulted in a lowering of the threshold for NMDA receptor-dependent signaling required for plasticity, leading to aberrant strengthening of excitatory synapses in spontaneously active neurons. PBM-deficient animals also exhibited a lower seizure threshold, disrupted LTP, and impaired cognition. Thus, the PBM enables isoform-specific SynGAP gating of NMDA receptor function, a mechanism linking synaptic signaling dynamics to network excitability and cognition.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jan 19 2020

Keywords

  • Autism spectrum disorder
  • Epilepsy
  • Intellectual disability
  • Long-term potentiation
  • PDZ domain
  • PSD95
  • Synapse
  • SynGAP
  • Syngap1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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