Gene tied to energy production in brain could lead to new treatment for cognitive disorders

BUFFALO, N.Y. ­— Researchers in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo have discovered a connection between a specific gene and healthy brain function.

“The hope is that this discovery could eventually lead to expanded treatment for psychiatric and neurological disorders such as schizophrenia, bipolar disorder and autism,” explains Mikhail V. Pletnikov, MD, PhD, professor and chair of the Department of Physiology and Biophysics, the senior author of the study with Kateryna (Kate) Murlanova, PhD, the first lead author and a research scientist in the department. It was published Wednesday in Science Advances.

They discovered that the NPAS3 gene expressed in astrocytes — the cells that help with brain chemistry— regulate the energy production required to support thinking and memory.

NPAS3 is a transcription factor, which means it directs how certain genes work and influences how cells function.

“Previous studies have linked NPAS3 to conditions involving cognitive problems, such as schizophrenia, but scientists didn’t know exactly how it might be involved,” Pletnikov says.

When Pletnikov, Murlanova and their collaborators removed NPAS3 from astrocytes in mice, the astrocytes generated less energy; as a result, the mice performed poorly on learning and memory tests.

While astrocytes have long been considered passive support cells, the researchers say they are now being recognized for playing a crucial role in brain metabolism and overall function.

“This study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondria bioenergetics and cognitive function,” Murlanova explains.

She adds that their findings provide insights for more precise targeted treatment of cognitive dysfunction in neuropsychiatric diseases, which has traditionally proved challenging.

When the researchers gave the mice lactate, a product of cellular energy metabolism, it largely corrected the memory problem, and the mice improved on learning and memory performance tests.

“Many people think of lactate as something associated with exercise, but the brain uses lactate, too,” Pletnikov says.

Pletnikov began studying the NPAS3 gene more than 10 years ago when he was on the faculty at Johns Hopkins University. His collaborators discovered a gene mutation in a  family whose members had severe neurological and psychiatric disorders. They suspected that an insufficiency of NPAS3 was a factor.

This genetic discovery spurred Pletnikov to shift his research to studying the role of glial cells — non-neuronal support cells in the nervous system — in psychotic disorders with a particular focus on metabolic alterations and mitochondria.

While many genes identified for psychiatric disorders were initially studied only in neurons, glial cells like astrocytes, which constitute about 50% of brain cells, are also important for understanding these disorders, Pletnikov notes.

Murlanova worked as a trainee at Johns Hopkins under Pletnikov and then joined his lab at UB. She focuses on the genetic variants associated with brain and behavior development.

“I’m excited to be a leader in this groundbreaking research,” she says.

The next steps, Pletnikov says, involve tracing metabolism pathways and potentially showing that lactate can serve as an energy substrate for mitochondria when they are not functioning well.

He and Murlanova are writing a grant proposal for funding focused on mental health treatments. While he emphasized that lactate isn’t necessarily the next treatment for schizophrenia, the metabolic changes in glial cells, specifically in astrocytes, might provide new targets for treating psychiatric disorders.

Co-authors in the Jacobs School include Olga Pletnikova, MD, research associate professor in the Department of Pathology and Anatomical Sciences; Samir Haj-Dahmane, PhD, professor in the Department of Pharmacology and Toxicology; and Rebecca Howell, a MD-PhD student in the Department of Pharmacology and Toxicology.

Researchers from many other institutions contributed, including Roswell Park Comprehensive Cancer Center; the Danish Research Institute of Translational Neuroscience; Kyungpook National University, Daegu, Republic of Korea; the Korea Brain Research Institute; Johns Hopkins School of Medicine; Case Western Research University and Institutes for Transformative Molecular Medicine; the Brain Health Medicines Center in Cleveland, Ohio; and the Louis Stokes VA Medical Center in Cleveland.