| Abstract No.: | C-C3117 |
| Country: | Canada |
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| Title: | Effects of Medial Prefrontal Cortical Knock-down of Synapsin II on
Sensorimotor Gating, Social Behavior and Locomotor Activity in the Rat |
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| Authors/Affiliations: | 1 Bailee Dyck*; 1 Dr. Ram K. Mishra;
1 McMaster University, Hamilton, ON, Canada
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| Content: | Introduction: Synapsins are a family of neuron-specific synaptic vesicle-associated phosphoproteins, which have been implicated in neurotransmitter release and neuronal development. Mammalian synapsins are encoded by three distinct genes, synapsin I, II, and III, which give rise to at least 9 isoforms through alternate gene splicing. Synapsin II, specifically, is regulated by dopamine D1 and D2 receptor activation, and has been shown to be reduced in the medial prefrontal cortex of subjects with schizophrenia. Furthermore, chronic treatment with the typical antipsychotic drug haloperidol has resulted in subsequent increases in synapsin II mRNA and protein concentrations. Collectively, these results substantiate a possible role of reductions in synapsin II in the pathophysiology of schizophrenia. Therefore, the aim of this project was to generate rats with selective knock-down of synapsin II in the medial prefrontal cortex to further investigate this potential role of synapsin II in schizophrenia.
Materials and Methods: Successful knock-down of the synapsin II protein using antisense technology was first confirmed in vitro in primary cell cultures. Subsequently, synapsin II antisense deoxyoligonucleotides were continuously infused into the medial prefrontal cortex of male Sprague-Dawley rats for 14 days via osmotic mini pumps. After the two week infusion period, rats were monitored for commonly expressed behavioral abnormalities seen in putative preclinical animal models of schizophrenia, such as disruptions in prepulse inhibition and decrease social behavior. Successful selective protein knock-down was confirmed post-mortem using immunoblotting techniques.
Results: Treatment of primary cell cultures with synapsin II antisense sequences confirmed in a robust knock-down of the synapsin II protein. Rats with selective knock-down of synapsin II in the medial prefrontal cortex demonstrated significant deficits in prepulse inhibition at a 70 dB prepulse intensity when compared to surgical control animals (infused with artifical cerebral spinal fluid) (p=0.0207). No deficits in habituation to startle were detected, as commonly reported in established animal models of this disorder. Knock-down animals also displayed a robustly significant decrease in the amount of time spent interacting when compared to both surgical control (p=0.0028) and positive control (infused with sense oligonucleotides) (p=0.003) animals. Immunoblotting confirmed selective knock-down of both the synapsin IIa and IIb isoforms in the medial prefrontal cortex in post-mortem medial prefrontal cortex tissues only.
Conclusions: Rats with selective knock-down of the synapsin II protein in the medial prefrontal cortex demonstrate behavioral abnormalities commonly seen in putative preclinical animal models of schizophrenia. These results lend support to the notion that abnormalities in synapsin II expression may contribute to the pathophysiological mechanisms of schizophrenia. |
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