Behavioral abnormalities in synapsin II knockout mice implicate a causal factor in schizophrenia

Abstract

Recent studies on the phosphoprotein synapsin II have revealed reduced expression in postmortem medial prefrontal cortex tissues from subjects with schizophrenia, and chronic antipsychotic drug treatment has resulted in concurrent increases in synapsin II mRNA and protein levels. Collectively, this research suggests a role of synapsin II in the pathophysiology of schizophrenia; however, whether synapsin II plays a causal role in this disease process still remains unclear. Therefore, the goal of this investigation was to examine whether synapsin II knockout mice display behavioral abnormalities commonly expressed in preclinical animal models of schizophrenia, namely deficits in prepulse inhibition (PPI), decreased social behavior, and locomotor hyperactivity. Results indicate that mice with knockout of the synapsin II gene demonstrate deficits in PPI at three prepulse intensities (67, 70, and 73 dB), along with deficits in habituation to startle to a 110 dB acoustic pulse. Knockout animals also expressed decreased social behavior and increased locomotor activity when compared to wildtype and heterozygous populations. Complete knockout of the synapsin II gene was confirmed in postmortem brain tissues via immunoblotting. In conclusion, these results confirm that synapsin II knockout mice display behavioral endophenotypes similar to established preclinical animal models of schizophrenia, and lend support to the notion that abnormalities in synapsin II expression may play a causal role in the underlying pathophysiological mechanisms of schizophrenia.

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…(Barnes, 2000;Lionel et al, 2013;Weickert et al, 2004). Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004). Interestingly, alterations in the localization and function of DISC1 and neuregulin1 are linked to abnormalities of the NMDA receptor signaling complex that includes PSD95 (Balu and Coyle, 2011;Geddes et al, 2011;Ma et al, 2013;Schmitt et al, 2011).…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…Chronic treatment with the antipsychotic haloperidol, a dopamine D2 receptor antagonist, leads to increases in synapsin II mRNA and protein levels in rats and humans (Chong et al, 2006;Tan et al, 2014). Synapsin II KO mice exhibit behavioral abnormalities commonly seen in preclinical animal models of schizophrenia, including prepulse inhibition deficits, decreased social behavior, and locomotor hyperactivity (Dyck et al, 2009). These results implicate synapsin II in the pathophysiology of schizophrenia and as a possible target for novel therapeutics with less severe side effects.…”

Role of AP-2α Transcription Factor in the Regulation of Synapsin II Gene Expression by Dopamine D1 and D2 Receptors

“…Recently, we have also shown that synapsin II knockout mice exhibit behavioral abnormalities similar to preclinical animal models of schizophrenia produced by treatment with dopaminergic agents, such as D-amphetamine (Dyck et al 2007(Dyck et al , 2009). However, the transcription factors involved in the regulation of synapsin II gene expression by dopaminergic ligands have not been established.…”