Developmentally Regulated Switch in Alternatively Spliced SNAP-25 Isoforms Alters Facilitation of Synaptic Transmission

Abstract

Although the basic molecular components that promote regulated neurotransmitter release are well established, the contribution of these proteins as regulators of the plasticity of neurotransmission and refinement of synaptic connectivity during development is elaborated less fully. For example, during the period of synaptic growth and maturation in brain, the expression of synaptosomal protein 25 kDa (SNAP-25), a neuronal t-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) essential for action potentialdependent neuroexocytosis, is altered through alternative splicing of pre-mRNA transcripts. We addressed the role of the two splicevariant isoforms of SNAP-25 with a targeted mouse mutation that impairs the shift from SNAP-25a to SNAP-25b. Most of these mutant mice die between 3 and 5 weeks of age, which coincides with the time when SNAP-25b expression normally reaches mature levels in brain and synapse formation is essentially completed. The altered expression of these SNAP-25 isoforms influences short-term synaptic function by affecting facilitation but not the initial probability of release. This suggests that mechanisms controlling alternative splicing between SNAP-25 isoforms contribute to a molecular switch important for survival that helps to guide the transition from immature to mature synaptic connections, as well as synapse regrowth and remodeling after neural injury.

Reduced SNAP‐25 alters short‐term plasticity at developing glutamatergic synapses

“…SNAP-25 expression increases in wt [31] and in SNAP-25 het cultures during maturation in vitro (Fig 3H). Notably, at 21 DIV, when SNAP-25 expression was significantly increased, differences in evoked responses (eEPSC and eIPSC) and in shortterm plasticity disappeared (eEPSC (nA): wt ¼ 0.360 ± 0.023, Fig 2A), indicating that neurotransmission and short-term plasticity defects can be fully recovered in parallel with increases in protein expression.…”

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

“…Interestingly, in absence of this isoform, 75% of mice die before 5 weeks of age and surviving animals present alteration in synaptic maturation as well as deficit in synaptic transmission. 40 In addition, overexpression of SNAP25 in cultured hippocampal neurons resulted also in impaired synaptic transmission. 41 Altogether, these results suggest that an increased SNAP25b level might impair synaptic maturation or neurotransmission, which in turns might influence either the risk of developing BD or the AAO in vulnerable individuals.…”

Control of alternative pre-mRNA splicing by Ca++ signals

“…Examples include the neural cell adhesion molecule (NCAM) in axon guidance [102,[109][110][111][112][113], the synapse-associated protein of 25 kDa (SNAP25), NMDA receptor type I (NMDAR1), BK and Ca ++ channels and neurexin in synaptic function [8,96,108,[114][115][116][117][118][119][120][121][122][123], the intracellular plasma-membrane calcium-pump isoforms 2 and 4 (PMCA2 and 4) and inositol triphosphate receptor type 1 (IP3R1) in Ca ++ homeostasis [124][125][126][127][128][129][130][131][132], the caspase ICH-1 in neuronal survival/death [98,101,133], and the splicing factors Tra2 beta1 and Ania-6 in pre-mRNA splicing [99,106,[134][135][136] (Table 1).…”

“…Inclusion of these alternative exons regulates the subcellular localization of proteins or their functions [25,26,119,120,[127][128][129]123,125,134,[137][138][139][140][141], ranging from subtle changes such as current kinetics of ion channels to on or off switches in the sensitivity to protein kinases or hormones [26,114,139,[142][143][144] (Table 1). These observations suggest that the regulation of alternative splicing by Ca ++ signals has effects on the expression of genes involved in a variety of cellular functions, from cell adhesion molecules at the synapse, ion channels in the cellular endoplasmic membrane, caspase in the cytosol as well as splicing factors inside the nucleus.…”