GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons

Abstract

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

Delta glutamate receptor conductance drives excitation of dorsal raphe neurons

“…To assess involvement of GluD1R, we applied a channel-selective toxin. Akin to other Ca 2+ -permeable ionotropic glutamate receptors, GluDR channels are blocked by the Joro spider toxin, 1-Naphthyl acetyl spermine (NASPM) 5,19 . Application of NASPM (100 µM, 6 min) blocked the a1-AR-EPSC (96.0±12.5% reduction), which recovered to baseline after >30 min of wash ( Fig.…”

“…One theory is that they are scaffolding proteins or synaptic organizers strictly, rather than ion conducting channels. Although mutant forms and wild type channels have been reported to conduct 3,4,5 , conduction, gating, and biophysical properties of native GluD1R remain unexplored. Here we show that the inward current induced by activation of a1-adrenergic receptors (a1-ARs) in the dorsal raphe nucleus (DR) is mediated by GluD1R.…”

Standardized extract of Erythrina velutina Willd. attenuates schizophrenia-Like behaviours and oxidative parameters in experimental animal models

“…The schizophrenia affects about 1% of the world's population and it is defined as a neuronal syndrome with chronic transgression and disabling characteristics . Its pathophysiology is evidenced by mechanisms that involve neural oxidative imbalance, and it also includes the imbalance of neurotransmitters, such as dopamine and glutamate, such imbalances compromise brain function, leading to cell death …”

“…[1][2][3] Its pathophysiology is evidenced by mechanisms that involve neural oxidative imbalance, and it also includes the imbalance of neurotransmitters, such as dopamine and glutamate, such imbalances compromise brain function, leading to cell death. [1,4] This mental disorder is widely studied in the scientific community using the animal model induced by chronic administration of ketamine, an antagonist drug of the N-methyl-D-aspartate receptor (NMDAr), which mimics the pathophysiology of the disease, since there is a decrease in the NMDAr activity at the level of the central nervous system (CNS). [2,3,5] Due to this, the treatment of patients with schizophrenia is performed with antipsychotics that act on this dysfunction, divided into two groups, typical and atypical.…”

La famille delta des récepteurs du glutamate

“…Notamment, l'expression d'un GluD2 dominant négatif portant la mutation V617R (Val 617 mutée en Arg), connu pour inactiver la conduction ionique du canal des iGlu, abolit quasi totalement ce courant. Dans une étude publiée dans la revue Molecular Psychiatry [6], nous avons examiné l'activation de GluD1 par mGlu1/5 et son rôle dans la transmis- l'activité physiologique des neurones DA (Figure 1). De nombreuses études ont montré une association entre la présence de mutations dans les gènes codant GluD1/2 et des troubles psychiatriques.…”