α-Synuclein oligomers mediate the aberrant form of spike-induced calcium release from IP(3) receptor

Emerging evidence implicates α-synuclein oligomers as potential culprits in the pathogenesis of Lewy body disease (LBD). Soluble oligomeric α-synuclein accumulation in cytoplasm is believed to modify neuronal activities and intraneural Ca(2+) dynamics, which augment the metabolic burden in central neurons vulnerable to LBD, although this hypothesis remains to be fully tested. We evaluated how intracellular α-synuclein oligomers affect the neuronal excitabilities and Ca(2+) dynamics of pyramidal neurons in neocortical slices from mice. Intracellular application of α-synuclein containing stable higher-order oligomers (αSNo) significantly reduced spike frequency during current injection, elongated the duration of spike afterhyperpolarization (AHP), and enlarged AHP current charge in comparison with that of α-synuclein without higher-order oligomers. This αSNo-mediated alteration was triggered by spike-induced Ca(2+) release from inositol trisphosphate receptors (IP(3)R) functionally coupled with L-type Ca(2+) channels and SK-type K(+) channels. Further electrophysiological and immunochemical observations revealed that α-synuclein oligomers greater than 100 kDa were directly associated with calcium-binding protein 1, which is responsible for regulating IP(3)R gating. They also block Ca(2+)-dependent inactivation of IP(3)R, and trigger Ca(2+)-induced Ca(2+) release from IP(3)R during multiple spikes. This aberrant machinery may result in intraneural Ca(2+) dyshomeostasis and may be the molecular basis for the vulnerability of neurons in LBD brains.