In the brains of adult mice, communication through astrocyte networks controls the formation of spatial memories and plasticity in the hippocampus, a new study led by scientists at the Institute of Pharmacology and Toxicology at the University of Zurich (UZH) has found.

The UZH team led by Aiman Saab, PhD, and Bruno Weber, PhD, showed adult mice with astrocytes lacking two major channel proteins (connexins 30 and 43) that form specialized intercellular communication portals called ‘gap junctions’, exhibit abnormal neuronal excitability, synaptic transmission and long-term potentiation of neural signals in the CA1 region of the hippocampus, which together result in the complete inability to encode spatial memories.

“We found that in adulthood an intact astrocyte network is essential for neural homeostasis, synaptic plasticity and spatial cognitive abilities of this brain region,” said Saab, a senior author of the paper.

The findings were published on March 7, 2022, in the journal Cell Reports, in an article titled “Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning.”

Star-shaped glial cells called astrocytes or astroglia control passage through the blood-brain barrier, provide nutrients to nervous tissue, and support neural repair. Astrocytes work together with neurons to enable cognitive and behavioral functions of the brain. Just as neurons form neural networks through synaptic connections, astrocytes couple through membrane channels made of connexins that enable the exchange of ions and small molecules.

To understand the functions of the two major connexin proteins in the function of mature hippocampal circuits, the team developed a mouse model where connexins 30 and 43 are active during developmental stages but can be inactivated at adult stages through inducible Cre-mediated genetic recombination, selectively in astrocytes of the hippocampus. Once the genes encoding connexins 30 and 43 were turned off, astrocyte-to-astrocyte coupling was disrupted within a few weeks.

The authors observed, disruption of the astrocyte network altered the excitability of neurons and the transmission of signals through neural synapses in the hippocampus, accompanied by significant deficits in spatial learning and memory.

“Astrocyte functions are known to be involved in shaping cognitive abilities,” said Ladina Hösli, PhD, first author of the study. “Our study shows that an intact astrocyte network is critical for spatial memory formation in adult mice.”

The loss of astrocyte coupling also affects primary immune cells in the brain called microglia. The researchers show loss of astrocytic connexins and decoupling of astrocytic networks in the adult brain led to astrocyte and microglia activation throughout the brain. Similar aberrant microglial activation, a hallmark of inflammation in the brain, is also observed in neurodegenerative diseases such as Alzheimer’s disease and neuropsychiatric disorders like depressions.

Communication through astrocyte networks controls the formation of spatial memories and plasticity in the hippocampus [Hoesli et al, Cell Reports, 2022].

“Astrocytes and microglia not only changed their morphology, we also found alterations in specific markers that are characteristic to disease-associated microglia,” said Hösli. Using Sholl analysis that maps the complexity of microglial branches, the authors show decoupling astrocyte networks in mice resulted in increased complexity of microglial branches.

Age-related changes in the brain are also associated with changes in astrocytic coupling, suggesting astrocytic decoupling might contribute to age-related decline in learning and memory.

“Our study shows that in the adult brain the functioning of astrocytic connexins and an intact glial network may be important for the way astrocytes and microglia work together to maintain neural homeostasis,” said Saab.

A limitation of the study is that connexins serve functions beyond intercellular communication, which may play a role in the functional deficiencies observed in the mutant mice. The authors note, “the findings of this study could be influenced by a variety of molecular mechanisms, which require further investigation.”

In future experiments, the team will focus on how microglial functions change when astrocyte networks are disrupted.

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