Neuronal Menin Overexpression Rescues Learning and Memory Phenotype in CA1-Specific α7 nAChRs KD Mice

The perturbation of nicotinic cholinergic receptors is thought to underlie many neurodegenerative and neuropsychiatric disorders, such as Alzheimer's and schizophrenia. We previously identified that the tumor suppressor gene, MEN1, regulates both the expression and synaptic targeting of alpha 7 nAChRs in the mouse hippocampal neurons in vitro. Here we sought to determine whether the alpha 7 nAChRs gene expression reciprocally regulates the expression of menin, the protein encoded by the MEN1 gene, and if this interplay impacts learning and memory. We demonstrate here that alpha 7 nAChRs knockdown (KD) both in in vitro and in vivo, initially upregulated and then subsequently downregulated menin expression. Exogenous expression of menin using an AAV transduction approach rescued alpha 7 nAChRs KD mediated functional and behavioral deficits specifically in hippocampal (CA1) neurons. These effects involved the modulation of the alpha 7 nAChR subunit expression and functional clustering at the synaptic sites. Our data thus demonstrates a novel and important interplay between the MEN1 gene and the alpha 7 nAChRs in regulating hippocampal-dependent learning and memory.

Automated summary

The perturbation of nicotinic cholinergic receptors is thought to underlie many neurodegenerative and neuropsychiatric disorders. Previous research found that the tumor suppressor gene MEN1 regulates the expression and targeting of alpha 7 nAChRs. Knockdown of alpha 7 nAChRs initially upregulated and then downregulated menin expression, which could be rescued by exogenous expression of menin in hippocampal neurons, suggesting an important interplay between MEN1 gene and alpha 7 nAChRs in regulating hippocampal-dependent learning and memory.