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Disabling Gβγ-SNAP-25 interaction in gene-targeted mice results in enhancement of long-term potentiation at Schaffer collateral-CA1 synapses in the hippocampus

Irfan, Muhammada,d; Zurawski, Zackb; Hamm, Heidic; Bark, Christinaa; Stanton, Patric K.d

doi: 10.1097/WNR.0000000000001258

Three SNARE proteins, SNAP-25, syntaxin 1A, and VAMP2 or synaptobrevin 2, constitute the minimal functional machinery needed for the regulated secretion of neurotransmitters. Dynamic changes in the regulated release of neurotransmitters are associated with the induction of long-term plasticity at central synapses. In-vitro studies have validated the C-terminus of SNAP-25 as a target for inhibitory Gi/o-coupled G-protein coupled receptors at a number of synapses. The physiological consequences of the interaction between Gi/o proteins and SNAP-25 in the context of activity-dependent long-term synaptic plasticity are not well understood. Here, we report direct ex-vivo evidence of the involvement of the C-terminus of SNAP-25 in inducing long-term potentiation of synaptic strength at Schaffer collateral-CA1 synapses using a gene-targeted mouse model with truncated C-terminus (carboxyl terminus) of SNAP-25. It has been shown previously that truncation of the three extreme C-terminal residues in SNAP-25[INCREMENT]3 homozygote mice reduces its interaction with the inhibitory Gβγ subunits two-fold. In in-vitro hippocampal slices, we show that these SNAP-25[INCREMENT]3 mice express significantly larger magnitude of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses.

aDepartment of Molecular Medicine and Surgery, The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden

bDepartment of Anatomy and Physiology, University of Illinois at Chicago, Chicago, Illinois

cDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

dDepartment of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA

Correspondence to Patric K. Stanton, PhD, New York Medical College, Valhalla, NY 10595, USA Tel: +1 914 594 4883; fax: +1 914 594 4653; e-mail:

Received March 27, 2019

Accepted April 1, 2019

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