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Delta glutamate receptor conductance drives excitation of mouse dorsal raphe neurons
Journal article   Open access   Peer reviewed

Delta glutamate receptor conductance drives excitation of mouse dorsal raphe neurons

Stephanie C Gantz, Khaled Moussawi and Holly S Hake
eLife, Vol.9, e56054
04/01/2020
DOI: 10.7554/eLife.56054
PMCID: PMC7180053
PMID: 32234214
url
https://doi.org/10.7554/eLife.56054View
Published (Version of record) Open Access

Abstract

The dorsal raphe nucleus is the predominant source of central serotonin, where neuronal activity regulates complex emotional behaviors. Action potential firing of serotonin dorsal raphe neurons is driven via α1-adrenergic receptors (α1-AR) activation. Despite this crucial role, the ion channels responsible for α1-AR-mediated depolarization are unknown. Here, we show in mouse brain slices that α1-AR-mediated excitatory synaptic transmission is mediated by the ionotropic glutamate receptor homolog cation channel, delta glutamate receptor 1 (GluD1). GluD1R-channels are constitutively active under basal conditions carrying tonic inward current and synaptic activation of α1-ARs augments tonic GluD1R-channel current. Further, loss of dorsal raphe GluD1R-channels produces an anxiogenic phenotype. Thus, GluD1R-channels are responsible for α1-AR-dependent induction of persistent pacemaker-type firing of dorsal raphe neurons and regulate dorsal raphe-related behavior. Given the widespread distribution of these channels, ion channel function of GluD1R as a regulator of neuronal excitability is proposed to be widespread in the nervous system. Serotonin is a chemical that allows cells to communicate in the nervous system of many animals. It is also particularly important in the treatment of mental health disorders: a large number of antidepressants work by preventing nerve cells from clearing away serotonin, therefore increasing the overall level of the molecule in the brain. Yet, exactly how serotonin is released remains unclear.When a serotonin-producing cell is activated, a series of biochemical processes lead to the creation of an electric current that, ultimately, is required for the cell to release serotonin. This mechanism starts when the α1-adrenergic receptor, a protein at the surface of the cell, detects noradrenaline molecules. However, on its own, the α1-adrenergic receptor is unable to create an electric current: this requires ion channels, another type of protein which can let charged particles in and out of the cell. Here, Gantz et al. set out to determine the identity of the ion channel that allows noradrenaline signals to generate electrical activity in cells which can release serotonin.Electrical and chemical manipulation of mouse brain slices revealed that an ion channel called delta-glutamate 1 was active in serotonin-producing cells exposed to noradrenaline. In fact, applying toxins that specifically blocked the activity of this channel also prevented the cells from responding electrically to noradrenaline.Further experiments used mice whose serotonin-producing cells were genetically modified to turn off delta-glutamate 1. In turn, these animals showed anxiety-like behaviors, which could be consistent with a drop in serotonin levels. This is in line with previous human studies showing that patients with depression and other mental health conditions have mutations in the gene for delta-glutamate 1.Taken together, these results give an insight into the electrical activity of serotonin-producing cells. Further work is now required to examine how changes in the gene that codes for delta-glutamate 1 ultimately affect the release of serotonin. This could potentially help to understand if certain individuals may not be able to properly produce this chemical. As many antidepressants work by retaining serotonin that is already present in the brain, this knowledge could ultimately help patients who do not currently respond to treatment.

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