Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels

Abstract

In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca2+-dependent manner by a functional interaction with presynaptic Ca2+ channels, revealing a new role in synaptic transmission for synapsins.

Time-coded neurotransmitter release at excitatory and inhibitory synapses

“…For example, studies show that Syn I(II), known to coat synaptic vesicles and to have a postdocking role, regulates synchronous and asynchronous release (15). In particular, Syn II interacts directly with P/Q type and indirectly with N-type Ca 2+ channels to increase asynchronous release.…”

“…In contrast, the biomolecular processes generating asynchronous and spontaneous release remain unclear and controversial. However, experiments suggest multiple mechanistically distinct forms of asynchronous release operating at any given synapse, and these forms have been associated, for example, with vesicle-associated membrane protein 4 (VAMP4), synaptotagmin (Syt7), double C2 domain protein (Doc2) (still controversial), Rab3-interacting molecules (RIM) proteins, phosphoprotein isoforms synapsin (Syn I and Syn II), and endocannabinoids (eCBs) (11)(12)(13)(14)(15)(16). These views are still being debated due to fragmentary and conflicting data (reviewed in 17).…”

Knock-down of synapsin alters cell excitability and action potential waveform by potentiating BK and voltage-gated Ca2+ currents in Helix serotonergic neurons

“…The increased Ca 2+ permeability could also be related to the slightly decreased resting membrane potential (Condliffe et al, 2010) Medrihan et al (2013) showed functional interactions between SynII and presynaptic Ca 2+ channels (Cav2.1, a P/Q type channel) and an increased ratio of synchronous/asynchronous GABA release. In addition, a potential interaction of SynI and SynII with distinct voltage-gated Ca 2+ channels has been suggested by proteomic studies (Müller et al, 2010).…”

“…showing an imbalance between excitatory and inhibitory neurotransmission, reducing the GABAergic component and leaving unchanged or increased the glutamatergic component (Terada et al, 1999;Gitler et al, 2004;Baldelli et al, 2007;Chiappalone et al, 2009;Ketzef et al 2011;Farisello et al, 2012;Medrihan et al, 2013;Feliciano et al, 2013;Lignani et al, 2013;Medrihan et al, 2014), thus leading to an increased network excitability.…”

Subconvulsant doses of pentylenetetrazol uncover the epileptic phenotype of cultured synapsin-deficient Helix serotonergic neurons in the absence of excitatory and inhibitory inputs

“…It is generally accepted that Syn deficiency reduces GABAergic transmission and not affects or increases glutamatergic transmission, thus leading to a positive imbalance towards hyperexcitability (Terada et al, 1999;Gitler et al, 2004;Baldelli et al, 2007;Chiappalone et al, 2009;Ketzef et al, 2011;Farisello et al, 2012;Lignani et al, 2013;Feliciano et al, 2013;Medrihan et al, 2013;Medrihan et al, 2014 Klee, 1976 andAltrup, 2004). Finally, a key advantage of this monosynaptic cell model is that the presynaptic and postsynaptic compartments can be selectively targeted by injections and specific networks can be constructed by directly plating individual neurons on MEA electrodes.…”