A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity

Cell Rep. 2015 Jul 21;12(3):396-404. doi: 10.1016/j.celrep.2015.06.037. Epub 2015 Jul 9.

Abstract

Neurotransmitter release probability (P(r)) largely determines the dynamic properties of synapses. While much is known about the role of presynaptic proteins in transmitter release, their specific contribution to synaptic plasticity is unclear. One such protein, tomosyn, is believed to reduce P(r) by interfering with the SNARE complex formation. Tomosyn is enriched at hippocampal mossy fiber-to-CA3 pyramidal cell synapses (MF-CA3), which characteristically exhibit low P(r), strong synaptic facilitation, and pre-synaptic protein kinase A (PKA)-dependent long-term potentiation (LTP). To evaluate tomosyn's role in MF-CA3 function, we used a combined knockdown (KD)-optogenetic strategy whereby presynaptic neurons with reduced tomosyn levels were selectively activated by light. Using this approach in mouse hippocampal slices, we found that facilitation, LTP, and PKA-induced potentiation were significantly impaired at tomosyn-deficient synapses. These findings not only indicate that tomosyn is a key regulator of MF-CA3 plasticity but also highlight the power of a combined KD-optogenetic approach to determine the role of presynaptic proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockdown Techniques / methods
  • Humans
  • Mice
  • Mossy Fibers, Hippocampal / metabolism
  • Mossy Fibers, Hippocampal / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Neuronal Plasticity / physiology*
  • Optogenetics / methods
  • R-SNARE Proteins / genetics
  • R-SNARE Proteins / metabolism
  • R-SNARE Proteins / physiology*
  • RNA, Small Interfering / metabolism*

Substances

  • Nerve Tissue Proteins
  • R-SNARE Proteins
  • RNA, Small Interfering
  • STXBP5 protein, human