Role of MEN1 Gene and Menin Protein in Learning, Memory and Neurodegeneration
Learning and Memory
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AbstractAll nervous system functions rely on precise connectivity and synaptic plasticity between neurons. Insight into the fundamental mechanisms that derive synapse formation and maintenance, are therefore critical for our understanding of normal nervous system functions as well as for managing a host of developmental, neurological, psychiatric, and neurodegenerative disorders. MEN1 gene and its encoded menin protein, are thought to play a role in the formation, plasticity and maintenance of cholinergic synapses in the CNS; their precise involvement in the hippocampal-dependent learning and memory, however, remains to be determined. I present here the first direct immunohistochemical evidence for the presence of two epitopes of the menin protein, C-menin and N-menin in the human brain, and then demonstrate a direct involvement of MEN1 in learning and memory using a mouse model. To develop an understanding of menin’s role in the neurodegenerative model, its expression patterns were characterized in the Alzheimer’s disease (AD) model, and these were compared to the control human hippocampal tissue. In Chapter Two, I demonstrate the presence of menin in both AD and non-AD brains along with other elements of the synaptic machinery (postsynaptic density protein -PSD95 and synaptophysin), nicotinic acetylcholine receptors, and tau protein. To test the involvement of MEN1 gene in learning and memory, in Chapter Three, I first developed a CKO model and specifically deleted its expression from the CA1 using a viral vector approach. I then investigated the necessity and sufficiency criterion of menin specifically in CA1 region of the hippocampus for learning and memory by first testing the CKO animals in Chapter Four. This was achieved through stereotactic injections of AAV9 viral vector transfection approach. Finally, in Chapter Four, I tested the hypothesis that the reintroduction of the MEN1 gene into conditional knockout animals will restore previously observed deficit in their fear conditioning. Taken together, the data presented here provided the first direct evidence for the presence of menin in a human autopsied brain tissue, and then demonstrates the sufficiency and necessity of MEN1 gene for fear conditioning learning and memory.
CitationUlfat, A. K. (2022). Role of MEN1 Gene and Menin Protein in Learning, Memory and Neurodegeneration (Unpublished doctoral thesis). University of Calgary, Calgary, AB.
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