Investigating the Role of Synapsin II in Neurological Disorders Involving Dysregulated Dopaminergic Transmission

Abstract

Schizophrenia (SCZ) is a debilitating mental illness that affects roughly 1% of the world's population. Current theories about the etiology of this disease highlight disruptions in dopamine (DA) and glutamine. However, a more recent theory, the 'synaptic hypothesis' proposes that the fundamental pathology of this illness involves disruptions in synaptic transmission. The synapsins are a family of neuron specific phosphoproteins that play an important role in neurotransmitter release, synapse formation and maintaining a reserve pool of synaptic vesicles. Previous research has suggested that synapsin II has a role in the etiology of SCZ. For example, synapsin II mRNA is significantly reduced in the medial prefrontal cortex (MPFC) of patients, and synapsin II knockout mice display a variety of behavioural abnormalities which mimic human SCZ. Considering that SCZ may result from changes in the synapse, we wanted to further elucidate the role of synapsin II by measuring protein expression in post-mortem PFC samples. Overall, our results revealed that synapsin IIa and IIb are not significantly different between patients and controls, however, we hypothesize that synapsin II expression has been normalized in patients due to antipsychotic drug (APD) use. In fact, we discovered that treatment with atypical APDs significantly increases synapsin II in the prefrontal cortex (PFC) of patients, which may underlie the beneficial effects of these drugs. Another objective of our work was to investigate the expression of various presynaptic proteins in post-mortem samples from patients with Parkinson's disease (PD) Parkinson's disease, like SCZ, is an illness which involves dysregulated dopaminergic transmission and synaptic dysfunction. Therefore, we hypothesized that synapsin II might also be disrupted in patients with PD. Our results demonstrated that synapsin IIa and IIb are significantly reduced in the substantia nigra (SN), but not the striatum (STR) or PFC of patients, when compared to controls. Further, no changes were observed in the other synapsins (I or III), or synaptophysin, which suggests that synapsin II dysregulation may be specific to disorders which involve disruptions in dopamine (DA).