title: A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity.
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.
authors.affiliation: Department of Neurobiology, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Simon
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
authors.forename: Alma
authors.initials: A
authors.lastname: Rodenas-Ruano
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Alviña
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alice D
authors.initials: AD
authors.lastname: Lam
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stuenkel
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. Electronic address: pablo.castillo@einstein.yu.edu.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.affiliation: Department of Neurobiology, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: uriashery@gmail.com.
authors.forename: Uri
authors.initials: U
authors.lastname: Ashery
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D062308:Optogenetics / Q000379:methods; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D034741:RNA, Small Interfering; C484767:STXBP5 protein, human