Astrocytes regulate intensity of neuronal signals linked to learning and memory by sensing wakefulness.
Neuroscientists at Tufts University School of Medicine have discovered a new signaling pathway that directly connects two major receptors in the brain associated with learning and memory – the N–methyl–D–aspartate receptor (NMDAR) and the alpha 7 nicotinic acetylcholine receptor (a7nAChR) – which has significance for current efforts to develop drugs to treat schizophrenia. These findings demonstrate that astrocytes are the key element that functionally links these two receptors.

The study, “Septal cholinergic neuromodulation tunes the astrocyte–dependent gating of hippocampal NMDA receptors to wakefulness,” was published in the journal Neuron.

“The NMDAR is the most investigated receptor in neuroscience because it is essential to synaptic plasticity, which is instrumental in establishing and remodeling brain circuitry and is thought to be the cellular foundation of learning and memory,” said Thomas Papouin, PhD, research assistant professor at Tufts School of Medicine and lead author of the study. “The NMDAR is known to be activated by two chemicals: glutamate, which is supplied by neurons, and D–serine, which is supplied by astrocytes. While most research is focused on the role that neurons play in activating the NMDAR via glutamate, we focused on the role played by astrocytes through the release of D–serine.”

Using in vitro and in vivo approaches in mice, the Tufts scientists found that astrocytes adjust their release of D–serine according to the degree of wakefulness of the mice. The astrocytes directly monitor wakefulness via the a7nAChR by sensing the level of ambient acetylcholine, a neuromodulator released in human and rodent brains during wakefulness. The more active the mice, the more D–serine is released by astrocytes, which allows a more robust activation of NMDARs. This was true even if researchers stimulated activity during times of day when mice are normally quiet.

“Astrocytes act like the dimmer control of a light,” Papouin said. “When the neuronal switch goes on, and glutamate is released, the setting of the astrocytic D–serine ‘dimmer’ determines the intensity of the NMDAR signal. During wakefulness, this dimmer is set on high – astrocytes provide a lot of D–serine – and this allows for a strong NMDAR signal. But during sleep or inactivity, it is set on low, allowing for a weaker signal.”

The study offers a new functional framework for treating schizophrenia and opens fresh avenues for therapeutics and innovations in glial biology.