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

Kilinc, M.; Creson, T. K.; Rojas, C.; Maity, S.; Le, A. A.; Lauterborn, J.; Wilkinson, B.; Hartel, N.; Graham, N. A.; Reich, A.; Gou, G.; Araki, Y.; Bayes, A.; Coba, M. P.; Lynch, G.; Miller, C. A.; Rumbaugh, G.

doi:10.1101/2020.01.18.911487

bioRxiv · 10.1101/2020.01.18.911487

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

Kilinc, M.·Creson, T. K.·Rojas, C.·Maity, S.·Le, A. A.·Lauterborn, J.·Wilkinson, B.·Hartel, N.·Graham, N. A.·Reich, A.·Gou, G.·Araki, Y.·Bayes, A.·Coba, M. P.·Lynch, G.·Miller, C. A.·Rumbaugh, G.

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Abstract

SynGAP-1 is a splice variant of the neurodevelopmental disorder risk gene, SYNGAP1/Syngap1. 1 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-1 in response to NMDA receptor activation. Genetic disruption of the PBM increased SynGAP-1 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.

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Kilinc, M., Creson, T. K., Rojas, C., Maity, S., Le, A. A., Lauterborn, J., Wilkinson, B., Hartel, N., Graham, N. A., Reich, A., Gou, G., Araki, Y., Bayes, A., Coba, M. P., Lynch, G., Miller, C. A., Rumbaugh, G.. 2020-01-19. Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function. https://doi.org/10.1101/2020.01.18.911487

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