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Chronic over‐expression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice
Author(s) -
Vaden Jada H.,
Tian Tina,
Golf Samantha,
McLean John W.,
Wilson Julie A.,
Wilson Scott M.
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14630
Subject(s) - ubiquitin , synaptic plasticity , biology , ubiquitin ligase , nmda receptor , ampa receptor , hippocampus , hippocampal formation , receptor , microbiology and biotechnology , neuroscience , biochemistry , gene
Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA ( GRIA 1‐4) receptor expression without affecting the levels of NMDA ( GRIN ) or GABA A receptors. Ubiquitin over‐expression also negatively impacted hippocampus‐dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA 3‐ CA 1 synapses. These changes occurred in a dose‐dependent manner in that mice with the highest levels of ubiquitin over‐expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress‐induced changes observed in neurological disorders.