Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse

GLYNN, Dervila, GIBSON, Helen E., HARTE, Michael K., REIM, Kerstin, JONES, Susan, REYNOLDS, Gavin and MORTON, A. Jennifer (2010). Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse. Human Molecular Genetics, 19 (17), 3402-3412.

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Complexin 2 is a protein modulator of neurotransmitter release that is downregulated in humans suffering from depression, animal models of depression and neurological disorders such as Huntington’s disease in which depression is a major symptom. Although complexin 2 knockout (Cplx2-/-) mice are overtly normal, they show significant abnormalities in cognitive function and synaptic plasticity. Here we show that Cplx2-/- mice also have disturbances in emotional behaviours that include abnormal social interactions and depressive-like behaviour. Since neurotransmitter deficiencies are thought to underlie depression, we examined neurotransmitter levels in Cplx2-/- mice and found a significant decrease in levels of noradrenaline and the serotonin metabolite 5-HIAA in the hippocampus. Chronic treatment with clorgyline, an irreversible inhibitor of monoamine oxidase A, restored hippocampal noradrenaline to normal levels (from 60% to 97% of vehicle-treated Cplx2+/+ mice, p<0.001), and reversed the behavioural deficits seen in Cplx2-/- mice. For example, clorgyline-treated Cplx2-/- mice spent significantly more time interacting with a novel visitor mouse compared to vehicle-treated Cplx2-/- mice in the social recognition test (34% compared to 13%, p<0.01). We were also able to reverse the selective deficit seen in mossy fibre long-term potentiation (MF-LTP) in Cplx2-/- mice using the noradrenergic agonist isoprenaline. Pre-treatment with isoprenaline in vitro, increased MF-LTP by 125% (p<0.001) thus restoring it to control levels. Our data strongly support the idea that complexin 2 is a key player in normal neurological function, and that downregulation of complexin 2 could lead to changes in neurotransmitter release sufficient to cause significant behavioural abnormalities such as depression.

Item Type: Article
Research Institute, Centre or Group - Does NOT include content added after October 2018: Biomedical Research Centre
Identification Number:
Page Range: 3402-3412
Depositing User: Users 3084 not found.
Date Deposited: 14 Sep 2012 12:47
Last Modified: 18 Mar 2021 20:15

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