Hippocalcin Regulates NMDA Receptor Function and Neuronal Activity Through Elavl3 in Mouse Hippocampal Neural Precursor Cells

TL;DR

This study shows that Hippocalcin (HPCA) regulates NMDA receptors and neuronal activity in mouse hippocampal cells through Elavl3, impacting brain function and behavior.

Contribution

The study identifies Elavl3 as a novel downstream mediator of HPCA in regulating NMDA receptor function and neuronal development.

Findings

HPCA knockdown reduces NMDA receptor-related gene expression and calcium signaling in mouse hippocampal neural precursor cells.

Elavl3 suppression mimics HPCA deficiency, impairing NMDA receptor activity and neuronal differentiation.

HPCA knockdown in vivo alters locomotor activity, memory, and affective behaviors in mice.

Abstract

Hippocalcin (HPCA), a neuron-enriched calcium-binding protein, plays a critical role in brain function, but its role in neural precursor cells remains unclear. N-methyl-D-aspartate (NMDA) receptors are calcium-permeable glutamate receptors essential for neurodevelopment and synaptic plasticity, and their function has been implicated in neurological conditions. In this study, we investigated the role of HPCA in regulating NMDA receptor expression and function in mouse hippocampal neural precursor cells (mHNPCs). HPCA knockdown significantly reduced the expression of NMDA receptor-related genes, including Grin2C, Shank1, Serpine2, and selectively attenuated NMDA-induced calcium signaling. Transcriptomic analysis identified ELAV-like RNA-binding protein 3 (Elavl3), a neuron-enriched factor associated with neuronal activity, as a downstream candidate affected by HPCA knockdown. Consistently, Elavl3 suppression phenocopied HPCA deficiency, resulting in impaired NMDA receptor activity and reduced neuronal differentiation. Furthermore, hippocampal HPCA knockdown in vivo led to alterations in locomotor activity, contextual memory, and affective behaviors. Taken together, these findings demonstrate that HPCA supports NMDA receptor function and neuronal development, in part through Elavl3-associated pathways, and highlight HPCA as an important regulator of hippocampal function.

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