Virginia Tech scientists discover mitochondria’s role in shaping memory circuits

Virginia Tech neuroscientists have uncovered a mitochondrial process that supports the brain cells critical for learning, memory, and social recognition.

Led by Shannon Farris, assistant professor at the Fralin Biomedical Research Institute at VTC, the research in mouse models examines the hippocampal CA2 region, a specialized area in the brain’s memory center essential for social recognition memory.

Published this week in Scientific Reports, the study reveals the critical role of the mitochondrial calcium uniporter (MCU), a protein that regulates calcium flow into mitochondria, in enabling neurons to strengthen connections. This process, known as synaptic plasticity, is fundamental to cognitive function and adaptive learning.

“Our findings highlight a distinct mitochondrial mechanism that helps explain how CA2 neurons function, which may contribute to its role in social cognition and its vulnerability in certain neurological disorders,” Farris said.

A unique role for the CA2 region in social memory

The hippocampal CA2 region is a small but critical hub for social recognition — the ability to remember and distinguish individuals. Unlike neighboring hippocampal regions, CA2 neurons resist certain forms of synaptic plasticity, raising intriguing questions about their specialized function.

Farris and her team discovered that mitochondria in CA2 neurons are not uniform. Instead, their structure and function vary depending on their location within the neuron. Mitochondria in the farthest reaches of the dendrites of neurons — at the outermost synaptic input connections — are highly specialized and depend heavily on MCU to control their activity.

To explore this, the researchers deleted the MCU gene in CA2 neurons of genetically engineered mice. This caused a disruption in plasticity at the outermost synapses, while those closer to the cell body were unaffected.

“This suggests that mitochondrial diversity isn’t just a biological quirk,” said Farris. “It’s a fundamental feature that allows different parts of the same neuron to function in distinct ways.”

Potential implications for Alzheimer’s, autism spectrum disorder

Mitochondrial dysfunction is increasingly recognized as a major contributor to neurological disorders such as Alzheimer’s disease, autism, schizophrenia, and depression. 

Synapses need a lot of energy to stay connected and process information. When mitochondria don’t work properly, it can disrupt the functional capacity of these cell-cell communications channels , leading to problems with thinking and memory.

It is known that the most distal outermost synapses are among the first synaptic connections affected in Alzheimer’s disease. The findings suggest that MCU’s function in CA2 neurons may contribute to this initial weakness, offering potential insight into why this circuit is particularly susceptible to neurodegeneration.

“Understanding why mitochondria in CA2 neurons are different — and how they fail — could help us design therapies to protect or restore function in specific brain regions,” Farris said.

Beyond Alzheimer’s, the study raises broader questions about how mitochondrial diversity might influence other neurological disorders. The ability of neurons to fine-tune mitochondrial properties could be a critical factor in understanding autism, where CA2 dysfunction could be linked to the known social deficits that occur in this spectrum.

Decoding mitochondrial function in neural circuits

This study advances understanding of mitochondrial biology and overcomes a technical hurdle in assessing mitochondria in dense and diverse brain tissues, the researchers said.

Using electron microscopy and artificial intelligence to unbiasedly identify only the dendritic mitochondria within the densely packed synaptic layer, Farris’s team mapped mitochondrial structure in CA2 neuron dendrites at high spatial resolution with extreme precision over millimeterexpanses of tissue. The analysis revealed that MCU-deficient mitochondria were smaller and more fragmented, a structural shift that may underlie their impaired ability to support synaptic function.

More broadly, the study challenges the long-held assumption that mitochondria work the same way throughout all parts of the neuron. Instead, neurons may actively modify mitochondrial properties to optimize function at specific synapses, a concept that could reshape our understanding of neural energy regulation and plasticity.

“These findings challenge the long-held assumption that mitochondria function uniformly within dendrites,” said Katy Pannoni, a senior research associate in Farris’s lab and the study’s first author. “Instead, our work suggests that mitochondria are highly specialized to support the distinct needs of different neural circuits.”

By applying artificial intelligence to analyze large-scale electron microscopy datasets, the research team quantified mitochondrial structure and distribution across circuits at a scale unattainable by conventional manual methods. This new approach will allow future studies to investigate mitochondrial function with greater precision and depth of analysis.

The future of mitochondrial research

This discovery opens new pathways to consider for potential therapies, particularly for neurological disorders where energy deficits weaken brain connections. By revealing how mitochondria support neural plasticity, Farris’s research lays the groundwork for strategies to preserve brain function and slow neurodegeneration.

Next, her team will investigate how mitochondria in CA2 neurons develop their specialized properties and whether similar adaptations exist in other brain regions. They also aim to explore therapeutic strategies that could bolster mitochondrial health and protect neurons from disease.

“The more we understand mitochondrial diversity, the closer we get to unlocking how the brain learns, remembers, and adapts—and how we can keep it healthy," Farris said.

Farris is also an assistant professor in Virginia Tech’s Department of Biomedical Sciences and Pathobiology at the Virginia-Maryland College of Veterinary Medicine and the Virginia Tech Carilion School of Medicine Department of Internal Medicine.

All team members are part of the Fralin Biomedical Research Institute’s Center for Neurobiology Research.