, 2006). In cultured neurons, overexpression of the wild-type human protein at levels that do not produce deposits or obvious toxicity causes an inhibition of synaptic vesicle exocytosis as measured by optical imaging of both hippocampal and midbrain dopamine neurons (Nemani et al., 2010) (Figure 2). Modest
overexpression in transgenic mice produced a similar defect in neurotransmission measured by postsynaptic recording at hippocampal CA1 synapses (Nemani et al., 2010). It is also important to note that there was no change in quantal size. Several reports have shown that multimeric synuclein can form pores in artificial membranes in vitro (Rochet et al., 2004, Tsigelny et al., 2007 and Volles
Selleckchem VX770 et al., 2001). This should dissipate the H+ electrochemical gradient that drives neurotransmitter uptake into vesicles; however, the lack of change in quantal size argues further against pore formation by multimers, at least in these cells. Although previous work on the role of synuclein in transmitter release had identified major defects only in monoamine neurons, these findings indicated that the disturbance with overexpression is more general. Imaging further demonstrated a specific defect in exocytosis, with no change SKI-606 order in the endocytosis of synaptic vesicle membrane despite the effects on clathrin-dependent endocytosis observed in other cells (Ben Gedalya et al., 2009). In contrast to LDCV release by chromaffin cells (Larsen et al., 2006), the A30P mutation abolishes the effect of synuclein overexpression on synaptic vesicle exocytosis (Nemani et al., 2010). Presumably, the specific accumulation of synuclein at release sites (disrupted by the A30P mutation) is more important
for neurons, with many long processes, than for small, not compact chromaffin cells. However, electron microscopy in the transgenic mice overexpressing synuclein also showed a dispersion of synaptic vesicles away from the active zone and into the axon (Nemani et al., 2010), and it is more difficult to reconcile this observation with the accumulation of secretory granules at the plasma membrane in chromaffin cells that overexpress synuclein (Larsen et al., 2006). Recent ultrastructural analysis of a different transgenic mouse line has shown enlargement of boutons and convoluted internal membranes connected to the cell surface (Boassa et al., 2013). The precise nature of the defect in synaptic vesicle exocytosis remains unclear. Interestingly, the transgenic mice show a reduction in synapsins and complexin, consistent with a change in exocytosis. Subsequent work has also shown a defect in transmitter release with overexpression of synuclein in hippocampal cultures.