Layer-specific mitochondrial diversity across hippocampal CA2 dendrites

Abstract

CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2, however the functional significance of this enrichment remains unclear. The MCU complex regulates calcium entry into mitochondria, which in turn regulates mitochondrial transport and localization to active synapses. We found that MCU is strikingly enriched in CA2 distal apical dendrites, precisely where CA2 neurons receive entorhinal cortical input carrying social information. Further, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites, an effect also seen with genetically labeled mitochondria and electron microscopy. MCU overexpression in neighboring CA1 led to larger mitochondria preferentially in proximal dendrites compared to distal dendrites and controls, suggesting that MCU may act as a coincidence detector linking synaptic activity to mitochondrial morphology and function. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and implicate MCU expression in regulating mitochondrial mass and layer-specific dendritic localization. Functionally distinct mitochondria in CA2 distal dendrites may confer unique synaptic and circuit properties underlying CA2 function in social memory.