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. 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. Furthermore, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites, which was confirmed in CA2 with genetically labeled mitochondria and electron microscopy. MCU overexpression in neighboring CA1 led to a preferential localization of MCU in the proximal dendrites of CA1 compared to the distal dendrites, an effect not seen in CA2. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and suggest that MCU can be differentially localized within dendrites, possibly to meet local energy demands.

MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits

“…We confirmed our previous findings based on manual segmentation that mitochondria in SLM of CTL CA2 are significantly larger in area than mitochondria in SR (supplemental Fig. 2C; Area SR vs SLM: p < 0.0001) (see Pannoni et al, 2023). In CA2 SLM, the distance between neighboring mitochondria was significantly less than mitochondria in SO or SR (supplemental Fig 2D; NN Distance SR vs SLM: p < 0.0001; SO vs SLM: p < 0.0001).…”

“…Importantly, the AI performed similarly across cKO and CTL images (Error rate per 100 µm 2 : 2 in cKO; 1.7 in CTL), which allows us to confidently compare dendritic mitochondria across cKO and CTL mice. In addition, the AI analysis replicated what has been previously shown in wild-type CA2 with a genetic fluorescent mitochondrial tag as well as with manual segmentation of SEM images (Pannoni et al 2023). Others have made comparisons of 3D mitochondrial ultrastructure in SEM across nucleus accumbens (NA), CA1, cortex and dorsal cochlear nucleus (DCN) (Delgado et al, 2019).…”

“…It's thought that calcium influx via MCU may be a mechanism to couple neuronal activity to mitochondrial metabolism (Groten & MacVicar, 2022;Stoler et al, 2022), allowing neurons to rapidly adapt to changing energy demands. Previously, we found a striking enrichment of MCU in hippocampal area CA2 (Pannoni et al, 2023;, a subregion of the hippocampus that is critical for social memory (Hitti and Siegelbaum 2014; Stevenson and Caldwell 2014;Dudek, Alexander, and Farris 2016). In contrast to CA1 neurons, CA2 neurons are known for being resistant to tetanus-induced LTP (Zhao et al, 2007), likely due to robust calcium buffering and extrusion mechanisms (Simons et al, 2011;Carstens and Dudek, 2019).…”

“…We recently uncovered that the propensity for LTP in CA2 correlates with more mitochondrial mass and higher expression of MCU selectively in distal dendrites compared to proximal dendrites (Pannoni et al, 2023). The distinct enrichment of MCU in CA2 distal dendrites is not merely due to the increased mitochondrial mass there, as other mitochondrial markers, such as COX4, do not show the same level of enrichment as MCU in CA2 distal dendrites and do not differ between areas CA1 and CA2 (Pannoni et al 2023). Thus, we predicted that layer-specific enrichment of MCU in CA2 distal dendrites may be important for promoting plasticity in otherwise LTP-resistant CA2 neurons.…”

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).…”