Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599446
Title: The role of complexins in neurological function in mice
Author: Glynn, D.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
Availability of Full Text:
Full text unavailable from EThOS. Please contact the current institution’s library for further details.
Abstract:
Complexins (CPLXs) are small, cytoplasmic proteins that modulate exocytosis of neurotransmitters via an interaction with the SNARE complex. A progressive decrease in expression of CPLXII protein has been detected in brain tissue from Huntington’s disease (HD) cases and from a mouse model of HD. To examine the possibility that depletion of Cplx2 (and later Cplx1) contributes to the abnormal neurological phenotype in R6/2 mice, the behaviour of Cplx1 and Cplx2 knockout mice was characterised. This was done using a battery of behavioural tests designed to detect motor, cognitive and social behaviours. In Chapter 3, Cplx2 knockout (Cplx2-/-) mice were shown to exhibit progressive deficits in both motor and cognitive behaviours. Although Cplx2-/- mice appeared outwardly normal, they show abnormalities in a number of complex behaviours including exploration, social interaction, motor co-ordination, learning and reversal learning. Some of the deficits measured, in particular the abnormalities in reversal learning, were strikingly similar to those described previously in the R6/2 line. Thus, CplxII appears to be critical for the acquisition of higher cognitive functions in adult mice. This supports the idea that depletion of this protein contributes to neurological dysfunction in HD. In Chapter 4, the postural and sensorimotor development of Clpx1-/- mice was assessed in the first three weeks after birth. While Cplx1-/- mice showed normal development in the first post-natal week, they developed a pronounced ataxia at around postnatal day 7. Other deficits were measured in the acquisition and performance of locomotor and exploratory behaviours over the next two weeks. Early deficits in motor behaviour are frequently due to abnormalities in the development of the cerebellum. However, there is no cerebellar pathology in Cplx1-/- mice. Thus the ataxia and other behaviour deficits seen in Cplx-/- mice are likely to be due to functional rather than structural deficits of the brain. In Chapter 5, the behaviour of adult Cplx1-/- mice was characterised. Cplx1-/- mice exhibited a complex neurological phenotype that included the motor deficits already seen in neonates, with additional deficits in social interaction and cognitive function. The profound deficits seen in the Cplx1-/- mice suggest that Cplx1 plays a key role in neurological function in normal mice. Further, they suggest that even a small depletion, of Cplx1 such as that seen in the late stage of the R6/2 mice, would contribute deleteriously to neurological function in these mice. To investigate further the role of CplxII depletion in the neurological phenotype of the R6/2 mouse, Cplx2-/- mice were cross-bred with R6/2 mice to give offspring that carried the HD mutation on Cplx2-/- background. A number of behavioural parameters measured were worse in the R6/2/Cplx2-/- mice than in the parent lines. However, these effects were not pronounced. This suggests that while it is important, loss of CplxII is not a central cause of the behavioural deficits in the R6/2 mouse. The most important findings in this thesis show that CplxI and CplxII both play essential roles in normal neurological function in mice. It is particularly notable that both Cplx1-/- and Cplx2-/- mice exhibit, to different degrees, deficits in ‘intermediate’ traits such as social interaction, motor and cognitive function. Such deficits are characteristics of a number of psychiatric disorders including schizophrenia, bipolar disorder and depression. Interestingly, all of these diseases involve alterations in CPLX expression. Thus, Cplx1-/- and Cplx2-/- mice may provide novel models in which intermediate traits of these disorders may be studied.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.599446  DOI: Not available
Share: