Presynaptic plasticity: A hiatus in neuroscience, a hotspot for Brain disorders

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Alexander J.A. Groffen

Dept. of Functional Genomics and Clinical Genetics, VU University and VU Medical Center, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands

: J Spine Neurosurg

Abstract

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Defects in synaptic strength and plasticity underlie many brain diseases, as illustrated by many recent findings from whole exome sequencing, but it remains a challenge to study the functional effect of clinically observed mutations in established models for neurotransmission. These studies typically focused on ‘classical’ fast neurotransmission that is evoked by actionpotentials (APs). We recentlydiscovered that AP-independent events, historically referred to as ‘spontaneous’ events, arein fact triggered by local Ca2+ increases that rely on specialized Ca2+ sensor proteins. In contrast to classical fast neurotransmission, genetic ablation of AP-independent neurotransmission produces viable neurologicalphenotypes and is therefore potentially relevant for disease gene characterization. Using whole-cell patch clamp electrophysiology in mammalian neurons, we refined our current working model by incorporating the contributions of classical and AP-independent neurotransmission. This cellular model was applied to investigate the synaptic effect of clinically observed mutations implicated in movement disorders, epilepsies, cognitive and autism-related disorders. The resultsprovide valuable insight to expand our map of the presynaptic gene network and shed more light on the etiology of several brain disorders. The results may facilitate disease classification based on moleculardiagnostics in future health care.

Biography

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