Shannon Farris, PhD, a principal investigator at the Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion

A team of researchers has published evidence showing in mice that mitochondria-associated pathways in cell bodies and dendrites within the CA2 subregion of the brain’s hippocampus influence plasticity and mitochondrial respiration—a finding that highlights a potential molecular target for treating human neurodegenerative disorders ranging from autism to Alzheimer’s disease.

In a study published yesterday, the researchers identified mitochondria as a regulator of CA2 through its role in buffering calcium, which plays a key role in cell-to-cell communication. Researchers also reported their discovery that each major subregion of the adult mouse hippocampus expresses a unique complement of dendritic RNAs, with RNA expression and alternative splicing differing by cell type and compartment within regions of the hippocampus.

Some of those differences in RNA expression and alternative splicing may be explained by differences within interneuron and non-neuronal cells present in dendritic laminae.

Researchers disclosed their findings in “Hippocampal Subregions Express Distinct Dendritic Transcriptomes that Reveal Differences in Mitochondrial Function in CA2,” published in Cell Reports.

“Given CA2’s role in social memory, it’s likely that other brain areas are involved in other autism phenotypes, such as motor areas like striatum, and repetitive behavior, but this highlights our current thinking that dysfunction in specific brain areas may underlie specific disease phenotypes,” Shannon Farris, PhD, the study’s lead author, told GEN.  “Now, we know it goes a step further, that different cell types within a brain area may be differentially affected too.”

Farris is now a principal investigator at the Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion in Roanoke, VA. Her lab focuses on understanding the molecular and cellular mechanisms underlying learning and how these processes are disrupted in neurodevelopmental disorders.

Farris carried out research while a postdoctoral researcher in the lab of Serena M. Dudek, PhD, the study’s corresponding author. Dudek is deputy chief of the Neurobiology Laboratory, principal investigator and head of the Synaptic and Developmental Plasticity Group at the NIH’s National Institute of Environmental Health Sciences in Research Triangle Park, NC.

Generating transcriptomes

Dudek, Farris, and colleagues carried out laser capture microdissection on three adult male Amigo2-EGFP mice, generating Hippocampal cell-type and compartment-specific transcriptomes with stranded, paired-end reads of sufficient depth to perform robust differential gene and isoform analyses. The cell body and dendritic layers from CA1, CA2, CA3, and DG were multiplexed per mouse (eight regions per mouse) and each sequenced on an Illumina NextSeq500 sequencer.

Such a study has only been possible in recent years because researchers have only lately been able to specifically access CA2 neurons, to study what genes are involved in these types of memories in the rodent, Farris said. While the hippocampus is involved in other functions, it is most linked specifically to experience-dependent memory and spatial navigation. Perhaps other functions that affect memory could be exacerbated by hippocampal dysfunction—for example, sleep, which is disrupted in numerous neurological disorders.

In their study, the researchers described more than 1,000 differentially expressed dendritic RNAs, suggesting that RNA localization and local translation are regulated in a manner specific to each cell type. The researchers focused their gene-ontology analyses on the CA2 region of the hippocampus given its resistance to plasticity and resistance to cell death, Farris said.

Investigators found that each hippocampal subregion expresses a unique complement of dendritic RNAs that is distinct compared with neighboring subregions, then created a website (http://splicejam.vtc.vt.edu) for researchers worldwide to visualize and mine these differences across hippocampal cell types and compartments.

“Unforeseen differences”

“By focusing our analyses on CA2, we discovered unforeseen differences in mitochondrial calcium handling and respiration as being important for CA2 plasticity and function,” the researchers stated in the study. “We anticipate that this data-set will continue to provide insights regarding cell type-specific regulation in the hippocampus for the field to explore.”

How much do differences in mitochondria between the neurons in CA2 compared with CA1 and other regions of the hippocampus explain the differences in neurodegenerative disease, or in the severity of each of the diseases? “We have no idea,” Farris said. Only recently has the field discovered that mitochondria are different depending on brain cell type, though researchers have known longer about tissue-specific differences, such as skeletal muscle vs. liver.

She noted that just last week, a team of researchers led by Anu Suomalainen, MD, PhD, of the University of Helsinki, published a study in Cell Metabolism that showed in a mouse model of mitochondrial disease that the metabolic regulator Fibroblast growth factor 21 (FGF21) coordinated step-wise changes within the muscle cell and in other tissues of the body in the mouse and in humans to progress mitochondrial myopathy, including changes in glucose and lipid metabolism, weight loss, and brain defects.

“This is the first example of CA2 being implicated in mitochondrial disease, and it opens up many avenues of research into diseases where mitochondria are affected—Alzheimer’s disease, Parkinson’s disease, etc.—as well as disorders where CA2 function, i.e., social memory, may be impaired, such as autism spectrum disorder and schizophrenia,” Farris said.

The research was funded by a grant to Farris from the NIH’s National Institute of Mental Health (R00MH109626) and by a grant to Dudek from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES100221).

Among avenues for follow-up research, according to Farris, is understanding why and how CA2 cells develop mitochondrial differences and what impact they have on CA2 cell function in social memory.

“Researchers are starting with perturbing mitochondrial calcium buffering because we already linked it to CA2 plasticity,” Farris said. “Also, can we link the translation of specific dendritic RNAs (perhaps mitochondrial RNAs) to the plasticity underlying social memory? Can we restore social behavior by modifying mitochondria in CA2? Is there a link between mitochondrial function and CA2 resistance to cell death?”

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