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The Journal of Neuroscience, October 6, 2004, 24(40):8796-8805; doi:10.1523/JNEUROSCI.1940-04.2004

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

Christina Bark,¹ Frederick P. Bellinger,² Ashutosh Kaushal,² James R. Mathews,² L. Donald Partridge,² and Michael C. Wilson²

¹Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden, and ²Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

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.

Key words: SNARE; neuroexocytosis; synaptic development; neurotransmission; alternative splicing; plasticity

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Received May 18, 2004; revised August 27, 2004; accepted August 30, 2004.

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