Astrocytes found to directly regulate memory consolidation during sleep

Research has shown that a good night’s sleep has many benefits, including memory consolidation. How sleep enables the brain to strengthen memories is still not completely understood, but a new study published in Neuron reveals how astrocytes, brain cells known for supporting neurons and their functions, can directly regulate brain circuits involved in memory consolidation.

The work, conducted by researchers at Baylor College of Medicine and collaborating institutions, may have implications for epilepsy, Alzheimer’s disease and other disorders associated with memory problems. Furthermore, the findings provide evidence that astrocytes are much more than support cells for neurons – they also seem to directly regulate brain function.

Astrocytes have been implicated in learning and memory and in sleep regulation. In the current study, we investigated how their roles in sleep facilitate the storage of memories.”

Dr. Benjamin Deneen, corresponding author, professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery and director of the Center for Cancer Neuroscience, Baylor

Astrocyte shape, molecular characteristics and functions vary extensively across brain regions. For example, astrocytes found in the hippocampus look round, bushy and highly branched, while those in the brain’s white matter have elongated and streamlined shapes. It has become increasingly clear that this diversity is key for astrocytes fulfilling their distinct roles throughout the brain.

“Recent evidence suggests that astrocytes’ heterogeneity is determined in part by proteins called transcription factors,” said first author of the work Sanjana Murali, graduate student in the Deneen lab. “Our previous work had revealed that more than 80% of astrocytes in the adult brain express transcription factor NFIX. Here, we explored whether it contributes to their function.”

The researchers knocked out the Nfix gene only in mature astrocytes in mice, throughout the entire brain. Because astrocyte function is tied to its shape, the team conducted the initial screening of the effect of deleting Nfix by looking for changes in astrocyte shape in each brain region.

“We found that shape complexity was reduced only in astrocytes located in the thalamic reticular nucleus (TRN) – the cells were shorter and with fewer branches than those in the TRN of animals with the Nfix gene. Without Nfix, astrocytes in this specific brain region became less complex and less connected to surrounding cells. In contrast, astrocytes from the hippocampus, olfactory bulb, brainstem and spinal cord showed no significant differences.”

The consequences extended beyond cell structure. Although the mice maintained relatively normal sleep patterns overall, they showed altered brain oscillations associated with sleep, suggesting that their neural activity had been affected. These mice had memory problems. They performed poorly on several tasks that measure working memory, object recognition and spatial memory. However, they did not show widespread problems with movement, anxiety, depression-like behavior or sensory processing. This suggests that Nfix loss specifically impairs memory-related functions associated with sleep rather than causing a broad decline in brain activity.

“We also looked into the molecular mechanisms involved,” Murali said. “We found that Nfix coordinates two parallel pathways involving the neurotransmitter GABA, which is important for astrocyte-neuron communication. One pathway depends on protein MAOB for GABA synthesis and the other relies on protein P2RX7 for GABA release.

When Nfix is absent, the levels of both MAOB and P2RX7 drop. Consequently, astrocytes synthesize and release less GABA. This weakened a form of neuronal inhibition known as tonic inhibition, which normally helps keep thalamic neurons functioning within an optimal range. Without sufficient tonic inhibition, the neural activity in the TRN was disrupted and memory consolidation impaired. Restoring either MAOB or P2RX7 in Nfix-deficient astrocytes resulted in a partial recovery of both normal neural signaling and memory performance.

“Altogether, the findings identify region-specific roles for astrocytic Nfix and its gene regulatory network in TRN astrocytes,” said Deneen, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and a principal investigator at the Duncan Neurological Research Institute at Texas Children’s Hospital. “We also reveal that astrocytes in the TRN couple regulation of TRN dynamics and memory formation through parallel GABA signaling pathways. This study supports a more holistic view of how to treat brain disorders. It’s not just about how neurons or astrocytes or other brain cells operate in isolation, but rather how their activities are coordinated and how this coordination is essential for proper brain function”

Other contributors to this work include Manuel Silva-Pérez, Junsung Woo, Priyanka Patel, Yeunjung Ko, Wookbong Kwon, Kaitlyn Sánchez, Henrique Borges da Silva, Richard Gronostajski and Jeannie Chin. The authors are affiliated with Baylor College of Medicine, Mayo Clinic or University of Buffalo.

This work was supported by US National Institutes of Health (grants R35-NS132230,1R01-AG071687 and R01-AG065290), the David and Eula Wintermann Foundation and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Award Number P50HD103555).