Rescue of learning and memory deficits in the human non-syndromic intellectual disability cereblon knockout mouse model by targeting the AMPK-mTORC1 translational pathway.

A homozygous nonsense mutation in the cereblon () gene results in autosomal recessive, non-syndromic intellectual disability (ARNSID) 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 maleknockout () mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knockout 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 thatis robustly expressed in the mouse hippocampus andmice exhibit hyperphosphorylated levels of AMPKα (Thr172). Examination of processes downstream of AMPK finds thatmice 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 UPR or autophagy pathways. Acute pharmacological inhibition of AMPK activity in adultmice 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 ofresults 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, non-syndromic ID (ARNSID), characterized by IQ between 50 and 70, but devoid of other phenotypic features, serving as an ideal protein to study the fundamental aspects of learning and memory. Here, using the cereblon knockout mouse model, we show that cereblon deficiency disrupts learning, memory and synaptic function via AMPK 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 knockout mouse as a model of pure ID without the confounding behavioral phenotypes associated with other current models of ID.