A similar impairment in CA3 mossy fibre LTP in the R6/2 mouse model of Huntington's disease and in the complexin II knockout mouse

Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
European Journal of Neuroscience (Impact Factor: 3.18). 11/2005; 22(7):1701-12. DOI: 10.1111/j.1460-9568.2005.04349.x
Source: PubMed


Complexin II is reduced in Huntington's disease (HD) patients and in the R6/2 mouse model of HD. Mice lacking complexin II (Cplx2-/- mice) show selective cognitive deficits that reflect those seen in R6/2 mice. To determine whether or not there is a common mechanism that might underlie the cognitive deficits, long-term potentiation (LTP) was examined in the CA3 region of hippocampal slices from R6/2 mice and Cplx2-/- mice. While associational/commissural (A/C) LTP was not significantly different, mossy fibre (MF) LTP was significantly reduced in slices from R6/2 mice and Cplx2-/- mice compared with wild-type (WT) and Cplx2+/+ control mice. MF field excitatory postsynaptic potentials (fEPSPs) in response to paired stimuli were not significantly different between control mice and R6/2 or Cplx2-/- mice, suggesting that MF basal glutamate release is unaffected. Forskolin (30 microm) caused an increase in glutamate release at MF synapses in slices from R6/2 mice and from Cplx2-/- mice that was not significantly different from that seen in control mice, indicating that the capacity for increased glutamate release is not diminished. Thus, R6/2 mice and Cplx2-/- mice have a common selective impairment of MF LTP in the CA3 region. Together, these data suggest that complexin II is required for MF LTP, and that depletion of complexin II causes a selective impairment in MF LTP in the CA3 region. This impairment in MF LTP could contribute to spatial learning deficits observed in R6/2 and Cplx2-/- mice.

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Available from: A. Jennifer Morton, Jul 28, 2014
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    • "In R6/2 mice, polyglutamine aggregates in intranuclear and extranuclear inclusions appear early in the CA1 region, and then in neurons of the CA3 field and the dentate gyrus of the hippocampus (Morton et al., 2000). Abnormalities in hippocampal synaptic plasticity are already present by 3 weeks of age (Gibson et al., 2005), and cognitive deficits associated with hippocampal function are measurable by 4 weeks of age (Lione et al., 1999). These data, together with our results, suggest that the slow-down of theta rhythm described by us and others may be the consequence of pathophysiological changes in the hippocampus of R6/2 mice, and are likely to relate to the cognitive decline described previously in these mice. "
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    • "We used juvenile R6/2 mice to study ex vivo the processes of Htt aggregation and inclusion formation. R6/2 mice show progressive neurological impairments [32], [33], [34], [35] and the appearance of ubiquitinated inclusions precedes the appearance of measurable behavioral (motor and cognitive) phenotypic changes [25] and happens at around the same time as abnormalities in synaptic plasticity [36] and early changes in brain markers [37] are first seen. "
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    ABSTRACT: Abnormal insoluble ubiqitinated protein aggregates are found in the brains of Huntington's disease (HD) patients and in mice transgenic for the HTT mutation. Here, we describe the earliest stages of visible NII formation in brains of R6/2 mice killed between 2 and 6 weeks of age. We found that huntingtin-positive aggregates formed rapidly (within 24-48 hours) in a spatiotemporal manner similar to that we described previously for ubiquitinated inclusions. However, in most neurons, aggregates are not ubiquitinated when they first form. It has always been assumed that mutant huntingtin is recognised as 'foreign' and consequently ubiquitinated and targeted for degradation by the ubiquitin-proteasome system pathway. Our data, however, suggest that aggregation and ubiquitination are separate processes, and that mutant huntingtin fragment is not recognized as 'abnormal' by the ubiquitin-proteasome system before aggregation. Rather, mutant Htt appears to aggregate before it is ubiquitinated, and then either aggregated huntingtin is ubiquitinated or ubiquitinated proteins are recruited into aggregates. Our findings have significant implications for the role of the ubiquitin-proteasome system in the formation of aggregates, as they suggest that this system is not involved until after the first aggregates form.
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    • "Impaired learning that occurs before motor symptoms or neuron loss has also been described for mouse models of HD (Lione et al., 1999; Mazarakis et al., 2005; Van Raamsdonk et al., 2005). These behavioral abnormalities are accompanied by deficits in hippocampal LTP (Hodgson et al., 1999; Murphy et al., 2000; Usdin et al., 1999) and by reductions in mossy fiber potentiation (Gibson et al., 2005) and long-term depression (Milnerwood et al., 2006). "
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