Understanding the role of complexin 1 in neurological disorders through investigation of the phenotype of Cplx1-/- mice

• Main Author: Drew, C.
• Published: University of Cambridge 2007
• Subjects: 591.5
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598652

The focus of the work presented in this thesis was the behavioural characterization of complexin I knockout <i>(Cplx1^-/-)</i> mice. The overall aim was to gain a better understanding of the role of complexins in the brain. In chapter 3 the motor phenotype of <i>Cplx1^-/- </i>mice was investigated. <i>Cplx1^-/-</i> mice suffer from profound ataxia, dystonia and tremor in the absence of neurodegeneration. It was found that <i>Cplx1^-/- </i>mice have impairments on the rotarod and in neuromuscular strength, indicating that CPLX I is essential for normal motor function in mice. In chapter 4 it was found that in addition to their motor impairments <i>Cplx1^-/-</i> mice exhibit a number of deficits in complex behaviours. <i>Cplx1^-/-</i> mice showed exploratory deficits in both free and forced exploration paradigms. Further, they showed an abnormal ‘panic’ like response to novel stimuli such as confinement and exposure to water. By contrast, no evidence for an ‘anxiety-like’ phenotype was found. In chapters 4 and 5 social behaviour was investigated. Whilst basic cognitive function is intact, <i>Cplx1^-/-</i> mice have profound impairments in social behaviour, which encompass both social interactions and sexually motivated behaviours. In chapter 6 brain neurochemistry was investigated since disruption in dopaminergic neurotransmission contributes to many of the diseases where complexin changes occur. Together the results described in this thesis show that the severe motor phenotype of <i>Cplx1^-/-</i> mice is accompanied by impairments in a number of other complex behaviours. This indicates that not only is CPLX I essential for normal motor function but also that it is important in the control of higher order functions. It seems likely therefore, that the dysregulation in CPLX I expression seen in human diseases will contribute to the neurological symptoms seen. This may be particularly important in Huntington’s disease, Parkinson’s disease and schizophrenia, all of which present with a mixture of motor, cognitive and psychiatric abnormalities.