Role of astrocyte-based cholinergic neuromodulation in cognition and in the treatment of cognitive disorders

ABSTRACT Neurons are viewed as the cellular correlate of cognition and only target of clinical therapeutics, in part because manipulating neurons rapidly and directly alters behavior.

Yet, the human brain is also made of glial cells, which morphological and genetic complexification is a striking feature of the human brain.

Astrocytes, in particular, are now known to orchestrate many neural functions, crystalizing the possibility of a direct astrocyte contribution to cognitive functions and mental health.

However, a lack of understanding of the rules that govern astrocytes activity and their involvement in neural circuits has limited our ability to test this idea. Collective work recently showed that astrocytes transduce neuromodulatory information onto synaptic circuits.

Specifically, we found that ?7 nicotinic acetylcholine receptors (?7nAChRs) on astrocytes regulate the release of the astrocyte transmitter D-serine onto synapses.

Neuromodulation, in particular cholinergic signaling, permits behavioral adaptations to changes in the environment, and its alteration is linked to cognitive deficits in schizophrenia.

Coincidently, the ?7nAChR has focalized major drug development efforts in the past decade to restore the cognitive symptoms of patients with schizophrenia.

Here, we will take advantage of this new astrocyte-based ?7nAChR pathway to test the role of astrocytes in cognitive functions and pro-cognitive interventions, and elucidate the mechanisms through which neuromodulation is sensed and transduced by astrocytes at the cellular and molecular levels.

In doing so, we will test a set of general principles which we hypothesize govern input output fidelity in astrocytes (positional coupling).

In Aim 1, we will test the hypothesis that ?7nAChRs are located in the immediate vicinity of D-serine pools, directly linking Ca2+ influx through ?7nAChR channel activity to the Ca2+-dependent D-serine release machinery.

We will conduct fluorescence Ca2+ imaging studies to understand the spatial, temporal and molecular rules of ?7nAChR-mediated Ca2+ signals and their relation to D-serine release.

We will then map the physical association of ?7nAChR and D-serine pools in perisynaptic astrocytic processes, using electron microscopy.

In addition, we will conduct single-particle tracking studies to understand how the dynamic distribution of ?7nAChR at the surface of astrocytes, with respect to D-serine pools, is influenced by the binding of endogenous and exogenous ligands.

In Aim 2, we will generate cell-specific knockout mouse lines to selectively ablate ?7nAChR from astrocytes, excitatory neurons or inhibitory neurons in the brain, and canvas the contribution of each cell-types to characteristic behaviors supported by ?7nAChRs.

We recently showed that an ?7nAChR partial agonist tested in Phase-III clinical trials for the treatment of cognitive deficits in patients with schizophrenia, elevates D-serine levels in the mouse brain.

Based on our observations that inactivating astrocyte-based ?7nAChR signaling leads to specific alterations in D-serine levels and cognitive behavior, we will then test the hypothesis that astrocytes, but not neurons, enable the behavioral efficacy of cognitive enhancers tested in clinical trials, and that D-serine signaling is the circuit actuator of these effects.