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. Genetic knockdown of MCU in CA2 resulted in smaller mitochondria in CA2 distal dendrites, indicating that MCU expression plays a role in regulating mitochondrial mass in CA2. MCU overexpression in neighboring CA1 led to larger mitochondria preferentially in proximal dendrites compared to distal dendrites and GFP controls. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and that MCU expression cell-autonomously regulates mitochondrial mass, but layer-specific dendritic localization depends on cell type. Our data support the idea that CA2 mitochondria are functionally distinct from CA1 mitochondria, which may confer unique synaptic and circuit properties underlying CA2 function in social memory.

Introduction to the special issue on: A new view of hippocampal area CA2

“…Among them are the mitochondrial calcium uniporters (MCUs), which are likely to contribute to the unique calcium dynamics in CA2 pyramidal neuron dendrites (Farris et al, 2019; Simons et al, 2009). Using state‐of‐the‐art imaging techniques, Pannoni et al (2023) follow‐up on this finding in this Special Issue with their discovery that the MCU‐enriched mitochondria are localized to the distal CA2 dendrites where axonal input from the entorhinal cortex forms synapses, suggestive of a novel type of calcium regulation in CA2 at those sites of contact. Also associated with this Special Issue is a manuscript by Samadi, et al, looking at the mechanisms underlying the particularly robust mGluR‐dependent long‐term synaptic depression in CA2, which include a reliance on RGS14 and the striatal enriched tyrosine phosphatase (STEP), which, recall, is also highly expressed in CA2 (Boulanger et al, 1995).…”