Xu, J. and Cohen, B. N. and Zhu, Y. and Dziewczapolski, G. and Panda, S. and Lester, H. A. and Heinemann, S. F. and Contractor, A. (2011) Altered activity–rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor. Molecular Psychiatry, 16 (10). pp. 1048-1061. ISSN 1359-4184 http://resolver.caltech.edu/CaltechAUTHORS:20111018-104112346
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High-affinity nicotinic receptors containing β2 subunits (β2^*) are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer's disease, Parkinson's disease and epilepsy. Mutations in both the α4 and β2 subunits are associated with a rare partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In this study, we introduced one such human missense mutation into the mouse genome to generate a knock-in strain carrying a valine-to-leucine mutation β2V287L. β2^(V287L) mice were viable and born at an expected Mendelian ratio. Surprisingly, mice did not show an overt seizure phenotype; however, homozygous mice did show significant alterations in their activity–rest patterns. This was manifest as an increase in activity during the light cycle suggestive of disturbances in the normal sleep patterns of mice; a parallel phenotype to that found in human ADNFLE patients. Consistent with the role of nicotinic receptors in reward pathways, we found that β2^(V287L) mice did not develop a normal proclivity to voluntary wheel running, a model for natural reward. Anxiety-related behaviors were also affected by the V287L mutation. Mutant mice spent more time in the open arms on the elevated plus maze suggesting that they had reduced levels of anxiety. Together, these findings emphasize several important roles of β2^* nicotinic receptors in complex biological processes including the activity–rest cycle, natural reward and anxiety.
|Additional Information:||© 2011 Macmillan Publishers Limited. Received 18 September 2009; revised 13 April 2010; accepted 4. June 2010; published online 6 July 2010. This work was supported by grants from NIH/NIDA (R01DA018247 to SFH, 5R01DA017279 to HAL), NIH/NEI (EY016807 to SP), NIH/NINDS (R01NS058894 to AC), NIH training awards (5T32NS041234-09 to JX, and 5T32EY007128-13 to YZ), and NS-011756 and NS-046464 to HAL. We thank Drs Michael Marks, Sharon Grady and Allan Collins for their suggestions.|
|Subject Keywords:||β2^* nicotinic receptor; ADNFLE; knock-in mouse|
|Official Citation:||Altered activity–rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor J Xu, B N Cohen, Y Zhu, G Dziewczapolski, S Panda, H A Lester, S F Heinemann and A Contractor Mol Psychiatry 16: 1048-1061; advance online publication, July 6, 2010; doi:10.1038/mp.2010.78|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Ruth Sustaita|
|Deposited On:||18 Oct 2011 18:19|
|Last Modified:||18 Oct 2011 18:19|
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