SNAP-25 isoforms differentially regulate synaptic transmission and long-term synaptic plasticity at central synapses

Muhammad Irfan,Omid Miry,Patric K Stanton,Christina Bark,Tomas Hökfelt,Katisha R Gopaul

doi:10.1038/s41598-019-42833-3

Muhammad Irfan, Omid Miry + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-42833-3

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Journal: Scientific Reports	Publication Date: Apr 25, 2019
Citations: 42	License type: open-access

Affiliation: Karolinska Institutet, New York Medical College

Abstract

SNAP-25 exists as two developmentally regulated alternatively spliced isoforms, SNAP-25a and SNAP-25b. We explored the function of SNAP-25a and SNAP-25b at Schaffer collateral-CA1 synapses in hippocampus using 4-week-old wild-type (WT) and SNAP-25b-deficient (MT) mice. Characterizing the protein expression of individual SNAP-25 isoforms revealed that WT females had higher levels of SNAP-25a than WT males, suggesting a sex-dependent delay of the alternative splicing switch from SNAP-25a to SNAP-25b. MT mice expressed normal levels of total SNAP-25, Syntaxin 1A and SNAP-47 in the hippocampus, but females expressed lower levels of VAMP2. Electrophysiological recordings in in vitro hippocampal slices revealed significantly reduced magnitude of LTP in MT mice. We also found reduction in paired-pulse facilitation after induction of LTP in WT males, but not in WT females, possibly related to the difference in SNAP-25a/SNAP-25b ratios, suggesting that the splicing switch may play a sex-specific role in LTP-associated increases in presynaptic release probability. Basal synaptic transmission measured in input-output relations revealed that the ability to discriminate between the intensity of presynaptic stimuli was affected in SNAP-25b-deficient mice. Learning in a behavioural paradigm of active-avoidance was impaired in MT mice, strengthening the conclusion that SNAP-25b is important for cognitive performance by altering activity-dependent synaptic plasticity.

Highlights

Cognate neuronal SNARE proteins comprising VAMP2, Syntaxin 1A and SNAP-25 that join to form the ternary SNARE complex enable neurotransmitter release[1]
Comparison of basal and post-long-term potentiation (LTP) paired-pulse facilitation (PPF) ratios of WT and MT mice revealed no significant differences in either sex (p = 0.09, Fig. 3c, p = 0.19, Fig. 3d, p = 0.20, Fig. 4c, p = 0.89, Fig. 4d). These results indicate that the relative expression ratios of SNAP-25a and SNAP-25b affect the induction of LTP and short-term presynaptic plasticity (STP) at Schaffer collateral-CA1 synapses in the hippocampus
Results of the PPF experiments revealed that the switch from SNAP-25a to SNAP-25b is associated with higher release probability after LTP

Summary

Introduction

Cognate neuronal SNARE proteins comprising VAMP2, Syntaxin 1A and SNAP-25 that join to form the ternary SNARE complex enable neurotransmitter release[1] This complex drives the process of fusion of intracellular vesicles with the plasma membrane, leading to exocytosis[2,3]. Studies from our laboratory and others have shown that ternary SNARE complexes containing SNAP-25b are more stable and heat resistant than complexes with SNAP-25a14–16 These previous findings might suggest that the two SNAP-25 isoforms play different roles in central neurons, with SNAP-25b being more important in consolidation of the mature synaptic network. The peripheral phenotype found in SNAP25b-deficient mice demonstrated sex differences, both in the amounts of insulin secreted and the severity of the metabolic syndrome[18,19]

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