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Compulsive Grooming and Hyperactivity in Nicastrin Conditional Knockout Mice
Author(s) -
Dries Daniel R.,
Zhu Julia,
Birnbaum Shari G.,
Yu Gang
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.813.3
Subject(s) - nicastrin , conditional gene knockout , forebrain , neuroscience , presenilin , knockout mouse , biology , central nervous system , alzheimer's disease , phenotype , psychology , disease , medicine , receptor , genetics , gene
The gamma‐secretase complex is a proteolytic machine of four subunits and is involved in the generation of the pathogenic and neurotoxic beta‐amyloid peptides found in the brains of Alzheimer's patients. Germline deletion of any of the four gamma‐secretase components results in embryonic lethality, necessitating tissue‐ and/or age‐specific deletion. Conditional deletion of presenilin (the catalytic subunit) or nicastrin (the substrate receptor subunit) from neurons in the mouse forebrain results in mild cognitive defects and neuronal loss. Here, we asked whether gamma‐secretase activity in other brain cell types (i.e. glia) also contributes to behavioral phenotypes. To this end, we have developed a conditional knockout mouse in which nicastrin has been specifically eliminated from oligodendrocytes, the myelinating cells of the brain. These mice are hyperactive and display reduced anxiety. Adult mice appear do not display gross brain pathology, although adult mice do have hypomyelination in the central nervous system. The work presented suggests that elimination of gamma‐secretase activity from oligodendrocytes may result in altered neuronal circuitry to elicit behaviors consistent with obsessive‐compulsive disorder and attention‐deficit‐hyperactivity disorder, as well as some of the non‐cognitive symptoms of Alzheimer's disease. Support or Funding Information This work was supported by NIH grants F32 AG031625, R01 AG023104, R01 AG029547, the Welch Foundation (I‐1566), the Hartwell Foundation, and the Alzheimer's Association.