Synapsin II Reductions and Schizophrenia: The Effects of Antisense Knockdown and Other Confounds on Disease Manifestation

Abstract

The complex heterogeneity of schizophrenia has proved difficult to replicate in preclinical animal models. Of the many molecular targets implicated with schizophrenia, this thesis focuses on synapsin II - a pre-synaptic protein critical for neurotransmission and synaptogenesis; and parvalbumin - a calcium-binding protein found in interneurons of the dorsolateral prefrontal cortex (DLPFC) and the striatum (STR). Patients with schizophrenia display reduced levels of synapsin II mRNA in the DLPFC, while decreased activation of parvalbumin neurons in the same region has resulted in schizophrenia-like cognitive deficits. Knockdown of synapsin II in the medial prefrontal cortex (mPFC) of neonate and adult rats has previously induced schizophrenia-like alterations. However, there are concerns that must be addressed before novel animal models of schizophrenia can be developed using reductions in synapsin II. This thesis was designed to 1) eliminate maternal separation (MS) between post-natal days (PD) 14-23, which correlates with a neurodevelopmental synapsin II model, as a means of inducing schizophrenia-like behaviours; 2) reassess the use of fully and partially phosphorothioated first-generation antisense oligonucleotides to reduce synapsin II levels, and 3) evaluate parvalbumin expression in the STR following synapsin II knockdown. Results from this study indicate 1) a 36 hour MS regimen during PD 14-23 did not cause behavioural changes bearing resemblance to schizophrenia; 2) oligonucleotide sequences stabilized completely with phosphorothioate bonds were insufficient in reducing synapsin II levels and caused localized necrosis, while partially modified sequences induced a slight knockdown effect without cell death; and 3) levels of striatal parvalbumin expression were decreased in rats receiving the partially, but not fully, modified antisense sequences. The findings strengthen the face validity and safety profile of the synapsin II knockdown model. Novel evidence has also been provided for the role of parvalbumin in the striatum and suggests its influence on cognitive dysfunction in schizophrenia.