title: Medial prefrontal cortical synapsin II knock-down induces behavioral abnormalities in the rat: examining synapsin II in the pathophysiology of schizophrenia.
abstract: Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in synapsin II mRNA and protein in medial prefrontal cortical post-mortem samples from patients with schizophrenia, genetic associations between synapsin II and schizophrenia, and synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of synapsin II in the medial prefrontal cortex. After continuous infusion of synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that synapsin II may potentially serve as a novel therapeutic target for this disorder.
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada, L8N 3Z5.
authors.forename: Bailey A
authors.initials: BA
authors.lastname: Dyck
authors.forename: Michael G R
authors.initials: MG
authors.lastname: Beyaert
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ferro
authors.forename: Ram K
authors.initials: RK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001526:Behavioral Symptoms / Q000209:etiology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D007266:Inhibition, Psychological; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000502:physiology; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D055139:Sensory Gating / Q000187:drug effects; D012919:Social Behavior; D016704:Synapsins / Q000737:chemistry / Q000378:metabolism*; D050481:Vesicular Neurotransmitter Transport Proteins / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D016704:Synapsins; D050481:Vesicular Neurotransmitter Transport Proteins