Developmentally regulated switch in alternatively spliced SNAP-25 isoforms alters facilitation of synaptic transmission.
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 potential-dependent neuroexocytosis, is altered through alternative splicing of pre-mRNA transcripts. We addressed the role of the two splice-variant 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.
Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Christina
C
Bark
Frederick P
FP
Bellinger
Ashutosh
A
Kaushal
James R
JR
Mathews
L Donald
LD
Partridge
Michael C
MC
Wilson
D017398:Alternative Splicing; D000818:Animals; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D050825:Synaptosomal-Associated Protein 25
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D019426:Integrases