Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Abstract

Summary The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active)-phase that dissipates to sub-saturating levels during the light (sleep)-phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically-tested α7nAChR agonist successfully enhances NMDARs activation.

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

“…Clinical studies suggest treatment of schizophrenia with α7 nAChR agonists and positive allosteric modulators has resulted in improved cognition and reduced negative symptoms (Freedman 2014). Studies in rodent models of neuropsychiatric and neurodegenerative disorders have also implicated the α7 nAChR (Gass et al 2016; Lykhmus et al 2015; Papouin et al 2017; Plitman et al 2017). In addition, α7 nAChRs have been shown to regulate aggression through activation of dentate granule cells (Lewis et al 2017).…”

Investigating brain d‐serine: Advocacy for good practices

“…52 Finally, immunodetection of D-serine or its metabolizing enzymes can be performed following different procedures (EM, electron microscopy; IF, immunofluorescence; IHC, immunohistochemistry) but necessary controls should be run in order to ascertain the specificity of the signal as illustrated (modified with permission from 21 ) glutamate from glucose by blocking the conversion of oxaloacetate into α-ketoglutaric acid. Restoring the glia-neuron shuttling by providing the D-serine precursor to neurons is thus able to fully overcome the astrocyte poisoning with FAC.…”

“…Of course, these mentioned studies proposed a significant role of the NMDAR co-agonist despite that the actual real specificity of these compounds remains totally unknown since they were identified as prototype inhibitors of SR only from in silico and in vitro screening assays. Once expressed, boNT/B cleaves the vesicle-associated membrane synaptobrevin-2 (Sb2), a component of the SNARE complex, which is expressed in astrocytes 42,52,[66][67][68]70,90 thus impairing vesicular release. In an ongoing and yet unpublished work (Lecouflet, Potier, Dutar, Billard and Mothet, manuscript in preparation), we observe that all these compounds have unwanted off-target effects since they display similar dose-dependent inhibitory actions on NMDAR synaptic functions and LTP in both wild-type and SR −/− hippocampal slices whatever the mode of administration (bath applied or injected in a single astrocyte).…”

D-serine Measurements in Brain Slices or Other Tissue Explants

“…In addition to glutamate, the activation of the NMDAR requires the binding of a co-agonist on a dedicated binding site (Johnson and Ascher, 1987; Kleckner and Dingledine, 1988). The unconventional amino acid D-serine is the endogenous co-agonist of the NMDAR in numerous regions of the nervous system (see Papouin et al ., 2017a). It is also found abundantly in the liver and kidneys where its degradation and excretion take place (Montesinos Guevara and Mani, 2016).…”