Identifying mitochondrial mechanisms driving learning and memory

The National Institute of Mental Health (NIMH) awarded a $1,737,000 Project Grant under the Mental Health Research Grants program (CFDA 93.242) to Max Planck Florida Corp, doing business as Max Planck Florida Institute For Neuroscience. The 3-year project, starting September 1, 2024, aims to systematically investigate the synaptic energy logistics that enable the brain to process and store information. Specifically, the research will discover novel regulators that dictate the flexibility of local mitochondrial energy production in temporal and spatial scales relevant for synaptic plasticity formation and maintenance - the cellular basis of learning and memory. The project will utilize recent innovations in subcellular proteomics, CRISPR-based screening, and advanced methods to measure ATP synthesis and calcium handling in individual dendritic spines and mitochondria. Findings from this work are expected to provide new solutions for learning and memory disorders by filling the knowledge gap between mitochondrial mechanisms and cognitive behaviors.

Abstract

The overall goal is to understand the energy supply mechanisms of learning and memory. The human brain is a metabolically vulnerable organ, where even an acute interruption in energy supply leads to immediate cognitive impairment. This energy consumption is primarily at neuronal synapses, which require energy for diverse processes such as maintaining ION gradients, making new proteins, and transporting molecules. Because most synapses are placed far from their neuronal cell body, mere ATP diffusion is insufficient to cope with the immediate (MINUTES) and sustained (HOURS) energy demands of local biological processes - a local energy source is necessary. Consistent with this notion, my lab recently showed that mitochondria are locally stabilized in dendrites. Local impairment of stable mitochondria affects the ability of nearby spines to undergo synaptic plasticity, the cellular basis of learning and memory (rangaraju ET AL., cell 2019, bapat ET AL., biorxiv 2023). Therefore, spatially stable mitochondria are essential to fulfilling the constant local energy demands of synaptic plasticity formation and maintenance. In light of our recent unpublished data, we hypothesize that mitochondria synthesize ATP on-demand during synaptic plasticity, and the temporal and spatial coordination of mitochondrial energy production near synapses dictates synaptic plasticity in time and space. So far, the known mechanisms of mitochondrial energy production are primarily based on information averaged across all subcellular compartments, but how plasticity stimuli regulate subcellular energy supply near synapses is unknown. We at the rangaraju lab will discover novel regulators that dictate the flexibility of local mitochondrial energy production in temporal (MINUTES to HOURS) and spatial (MS of dendrite) scales relevant for synaptic plasticity formation and maintenance. To tackle this challenge, we combine recent innovations in subcellular proteomics and crispr-based screening in primary neuronal cultures. In addition, we have developed state-of-the-art methods to measure ATP synthesis and calcium handling in individual spines and mitochondria at high spatial and temporal resolution to characterize subcellular (dendrites, spines) regulation of mitochondrial energy production at different stages of synaptic plasticity. Lastly, we will characterize our newly identified mechanisms in vivo in behavioral assays during various forms of learning and memory (spatial, motor, short- and long-term). Overall, we will systematically investigate the synaptic energy logistics that allow the brain to process and store information. As mitochondrial dysfunction is often linked to memory and cognitive impairment, filling the knowledge GAP between mitochondrial mechanisms and cognitive behaviors will provide new solutions to learning and memory disorders.