MEX3C induces cognitive impairment in mice through autophagy inhibition.

Abstract

The muscle excess 3 (MEX3C) protein comprises one of two conserved KH hnRNP K homology domains of the Caenorhabditis elegans protein family, a gene involved in the metabolism of key RNAs at posttranscriptional levels during the development of C. elegans, but its function in mammals is unclear. In this study, we found that MEX3C plays a key role in learning and cognitive function. The learning and cognitive abilities of MEX3C-knockout (KO) mice were significantly decreased relative to those of wild-type (WT) mice in behavioral experiments, including the shuttle box, Morris water maze, and new object recognition. Nissl staining showed a decrease in the number of Nissl bodies and in the maturation of hippocampal and cortical neurons. A Western blot analysis of the neuron-specific nuclear (NeuN) protein NEUN protein showed that the expression of that protein was decreased, which was consistent with the results of Nissl staining. Of note, the expression of sequestosome I p62 and Parkin BCL-2-associated X (Bax) Bax and B-cell lymphoma-2 (Bcl-2) Bcl-2 proteins also showed a downward trend, suggesting that the MEX3C gene may cause a decrease in the number and maturity of neuronal cells by increasing apoptosis through the inhibition of autophagy. In addition, Golgi staining showed that the complexity of neurons in the hippocampus and cerebral cortex was reduced, and the postsynaptic density protein 95 and growth-associated protein (GAP-43) also showed different degrees of reduction. The KO of the MEX3C gene reduces the plasticity of synapses in various regions of the hippocampus, thereby affecting the function of the hippocampus and eventually causing the decline of cognitive function. On the other hand, compared with WT mice, MEX3C-KO mice showed increased anxiety-like behaviors in minefield and elevated plus maze tests.