TitleRescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase-mTORC1 Translational Pathway.
Publication TypeJournal Article
Year of Publication2018
AuthorsBavley CC, Rice RC, Fischer DK, Fakira AK, Byrne M, Kosovsky M, Rizzo BK, Del Prete D, Alaedini A, Morón JA, Higgins JJ, D'Adamio L, Rajadhyaksha AM
JournalJ Neurosci
Date Published2018 Mar 14

A homozygous nonsense mutation in the cereblon () gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male knock-out () mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior. Cellular studies identify deficits in long-term potentiation at Schaffer collateral CA1 synapses. We further show that is robustly expressed in the mouse hippocampus and mice exhibit hyperphosphorylated levels of AMPKα (Thr172). Examination of processes downstream of AMP-activated protein kinase (AMPK) finds that mice have a selective impairment in mediators of the mTORC1 translation initiation pathway in parallel with lower protein levels of postsynaptic density glutamatergic proteins and higher levels of excitatory presynaptic markers in the hippocampus with no change in markers of the unfolded protein response or autophagy pathways. Acute pharmacological inhibition of AMPK activity in adult mice rescues learning and memory deficits and normalizes hippocampal mTORC1 activity and postsynaptic glutamatergic proteins without altering excitatory presynaptic markers. Thus, this study identifies that loss of results in learning, memory, and synaptic defects as a consequence of exaggerated AMPK activity, inhibition of mTORC1 signaling, and decreased glutamatergic synaptic proteins. Thus, mice serve as an ideal model of intellectual disability to further explore molecular mechanisms of learning and memory. Intellectual disability (ID) is one of the most common neurodevelopmental disorders. The cereblon () gene has been linked to autosomal recessive, nonsyndromic ID, characterized by an intelligence quotient between 50 and 70 but devoid of other phenotypic features, making cereblon an ideal protein for the study of the fundamental aspects of learning and memory. Here, using the cereblon knock-out mouse model, we show that cereblon deficiency disrupts learning, memory, and synaptic function via AMP-activated protein kinase hyperactivity, downregulation of mTORC1, and dysregulation of excitatory synapses, with no changes in social or repetitive behaviors, consistent with findings in the human population. This establishes the cereblon knock-out mouse as a model of pure ID without the confounding behavioral phenotypes associated with other current models of ID.

Alternate JournalJ. Neurosci.
PubMed ID29459374
PubMed Central IDPMC5852658
Grant ListR21 DA041883 / DA / NIDA NIH HHS / United States
R01 DA029122 / DA / NIDA NIH HHS / United States
R21 DA042581 / DA / NIDA NIH HHS / United States
R01 DA042499 / DA / NIDA NIH HHS / United States
R01 DA041781 / DA / NIDA NIH HHS / United States