Puzzling Out Synaptic Vesicle 2 Family Members Functions

Abstract

Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or neurotransmitters transport or priming of SVs. Moreover, several recent studies highlighted the link between SV2 and different neuronal disorders such as epilepsy, Schizophrenia (SCZ), Alzheimer's or Parkinson's disease. In this review article, we will summarize our present knowledge on SV2A function(s) and its potential role(s) in the pathophysiology of various brain disorders.

Keywords: SV2 functions; SV2 protein; epilepsy; neurological diseases; neurotransmission.

Figure 1

Schematic view of post synaptic currents (PSC) and summary of Synaptic vesicle proteins 2A (SV2A) KO phenotype. (A) Spontaneous PSC or sPSC: an action potential in the presynaptic neuron (black) induces a sPSC in the postsynaptic neuron (brown). (B) Miniature PSC or mPSC: the generation of action potentials is blocked by Tetrodotoxin (TTX). If SVs exocytosis is functional, a single vesicle is release by the presynaptic neuron (black) and induces a mPSC in the postsynaptic neuron (brown). The mPSC reveals thus the “molecular machinery” of SV exocytosis while sPSC also reveals the link between vesicle exocytosis and the pre-synaptic action potential. (C) Evoked PSC or evoked postsynaptic currents (ePSC): an action potential is induced with an electrode (blue) in the presynaptic neuron (black). The postsynaptic neuron (gray) responds by producing an ePSC. In comparison to the sPSC, the ePSC recruits the maximal possibilities of SVs exocytosis. The analysis of SV2A KO phenotype is telling us that: (1) in physiological conditions, inhibitory PSC are affected negatively by the SV2A absence, both in amplitude and in frequency although excitatory PSC are modified only through increased frequency; (2) the absence of SV2A does not interfere with the molecular mechanism of the SV exocytosis process; and (3) when the synapse is pushed at its maximum of activity, both excitatory and inhibitory PSC are decreased in amplitude.

Figure 2

Summary of neurophysiological observations. WT condition (black box): at cellular level (blue box), inhibitory postsynaptic currents (IPSC) and EPSC of inhibitory neurons (in red) and excitatory neurons (in green) display characteristic amplitudes and frequencies. At tissue level (purple box), the inhibitory frequency is higher than the excitatory frequency to moderate global input. SV2A KO condition (brown box): at cellular level (blue box), amplitudes of IPSC and EPSC are reduced. At tissue level (purple box), the excitatory frequency is higher than the inhibitory frequency, leading to seizure onset and epilepsy.

Figure 3

Interaction model of SV2A and Stonin 2 with Synaptotagmin 1. (A) After fusion event, the C2B domain of Synaptotagmin 1 (green) interacts with SV2A (light blue) phosphorylated-T84 residue (orange) and Stonin 2 (dark blue) binds to both C2 domains of Synaptotagmin to initiate recycling. (B) SV2A and Stonin 2 bind to AP-2 (pink) to facilitate the formation of the endocytosis complex. (C) Synaptotagmin 1 binds to AP-2. Dephosphorylated SV2A keeps interaction with AP-2 to consolidate the endocytosis complex. (D) After endocytosis, the fusion competent vesicle presents Synaptotagmin 1 bond again to T84-phosphorylated SV2A. IC, Intracellular; EC, Extracellular.

Figure 4

Primary structures of SV2 proteins. In green: Synaptotagmin 1 binding domain. In blue: nucleotide binding domains. In orange: residues implicated in LEV binding. Purple lozenge: phosphorylated residues. Pink square: glycosylated residues. In red: residues of particular interest. EC, Extracellular; IV, Intravesicular; IC, Intracellular. (This figure was built using http://wlab.ethz.ch/protter/start/).