Journal Article

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

Dervila Glynn, Helen E. Gibson, Michael K. Harte, Kerstin Reim, Susan Jones, Gavin P. Reynolds and A. Jennifer Morton

in Human Molecular Genetics

Volume 19, issue 17, pages 3402-3412
Published in print September 2010 | ISSN: 0964-6906
Published online June 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq252
Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse

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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-hydroxyindoleacetic acid 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 with vehicle-treated Cplx2−/− mice in the social recognition test (34 compared with 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.

Journal Article.  5924 words.  Illustrated.

Subjects: Genetics and Genomics

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