When Kateryna Murlanova injected lactate into mice with impaired memory, something remarkable happened: their cognitive performance bounced back, nearly to normal levels. The animals, genetically altered to lack the NPAS3 gene in their astrocytes, had been struggling to navigate mazes and recall simple tasks—until this simple metabolic intervention. At the University at Buffalo’s Jacobs School of Medicine and Biomedical Sciences, Murlanova and her mentor, Mikhail V. Pletnikov, have uncovered a vital link between a single gene in brain support cells and the energy that fuels learning and memory. Their discovery, published in Science Advances, could reshape how we treat cognitive disorders like schizophrenia, bipolar disorder, and autism.
For decades, neurons have dominated neuroscience. But astrocytes—long dismissed as mere support cells—make up about half the brain’s cellular population and are now emerging as metabolic powerhouses. The NPAS3 gene, a transcription factor active in these cells, regulates mitochondrial energy production. When the team deleted NPAS3 in mouse astrocytes, the cells produced less energy, and the mice showed clear cognitive deficits. Dendritic spines—tiny protrusions crucial for neural connections—thinned out in the prefrontal cortex, a region central to decision-making and memory. The result? Impaired learning and memory, mirroring symptoms seen in human neuropsychiatric conditions.
What makes this study groundbreaking is the direct mechanistic link it establishes: NPAS3 in astrocytes controls mitochondrial bioenergetics, which in turn supports cognitive function. "This study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondria bioenergetics and cognitive function," says Murlanova, the study’s first author. Even more promising, when the researchers supplied lactate—a natural byproduct of glucose metabolism—the memory deficits were largely reversed. Lactate isn’t just a waste product; it’s a fuel the brain can use, especially when glucose metabolism falters.
Pletnikov’s journey with NPAS3 began over a decade ago at Johns Hopkins, where a family with a rare mutation and severe psychiatric symptoms first pointed to the gene’s importance. That clue led him to explore glial cells, not just neurons, in mental illness. Now at Buffalo, he and Murlanova are pioneering a new frontier: treating cognitive dysfunction by targeting brain metabolism in support cells. With about 50% of brain cells being glial, this shift could unlock therapies that have long eluded researchers.
The next phase involves mapping the precise metabolic pathways involved and testing whether lactate or similar compounds can safely boost brain function in disease models. If successful, this could lead to entirely new classes of treatments—ones that don’t just manage symptoms but address the energetic roots of cognitive decline. For millions living with neuropsychiatric disorders, the future may not lie in silencing neurons, but in fueling the cells that support them.