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Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes. We show that reductions in metabotropic glutamate receptor 3 (mGluR3), the main astrocytic glutamate receptor in adults, impair memory in females but enhance memory in males. Similarly, increases in astrocytic mGluR3 levels have sex-dependent effects and enhance memory in females. mGluR3 manipulations also alter spatial search strategies during recall in a sex-specific manner. In addition, acute chemogenetic stimulation of G i/o -coupled or G s -coupled receptors in hippocampal astrocytes induces bidirectional and sex-dimorphic effects on memory. Thus, astrocytes are sex-dependent modulators of cognitive function and may promote sex differences in aging and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: The beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement., Aims: Here, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core., Methods: Male and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing., Results: mGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement., Conclusions: These results indicate that ceftriaxone's effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.

Despite the increasing interest and efforts to prevent, treat, and control epilepsy and its clinical manifestation (seizure), the prevalence has not decreased due to incomplete understanding of its etiology. The present study aimed at determining the effect of prolonged febrile seizure (PFS) on the onset of seizure in pilocarpine rat model of temporal lobe epilepsy (TLE). After induction of PFS at postnatal day (PND) 14 in ten out of thirty pups, epilepsy was induced with 350 mg/kg of pilocarpine on PND 60 in the 10 rats with PFS and 10 from the saline group. Animals that met the criteria for TLE were then chosen for the study. Effects of PFS on status epilepticus and the development of spontaneous recurrent seizures (SRSs) were observed. The hippocampal synaptophysin, glial fibrillary acidic protein (GFAP) with metabotropic glutamate receptor 3 (mGluR3) expressions were also measured with LI Cor Tissue florescence, immunofluorescence and immunohistochemistry respectively. We found that PFS reduced the onset of status epilepticus, but had no influence on the development of SRSs. Also, there was no difference in the hippocampal expression of synaptophysin and GFAP between rats that had pilocarpine with or without background PFS. However, the mGluR3 expression was significantly higher in pilocarpine with PFS when compared to pilocarpine alone. Our result showed that PFS may lead to epilepsy. It is also obvious that epilepsy with or without PFS history affects neurochemical expression of synaptophysin, GFAP and mGluR3, hence these proteins may be good targets for drug therapy in reducing both the mortality and morbidity of the disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely distributed in the mammalian nervous system. Drugs that inhibit the inactivation of synaptically released NAAG have procognitive activity in object recognition and other behavioral models. These inhibitors also reverse cognitive deficits in animal models of clinical disorders. Antagonists of mGluR3 block these actions and mice that are null mutant for this receptor are insensitive to the actions of these procognitive drugs. A positive allosteric modulator of this receptor also has procognitive activity. While some data suggest that drugs acting on mGluR3 achieve their procognitive action by increasing arousal during acquisition training, exploration of the procognitive efficacy of NAAG is in its early stages and thus substantial opportunities exist to define the breadth and nature of this activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep-wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands. The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine- and phencyclidine-induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose-dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake-promoting effects in both rat strains, albeit smaller in the mGluR2-lacking Han Wistar rats, indicating both mGluR2 and mGluR3-mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4-9 Hz) and gamma (30-80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats. Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic-like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Several clinical studies have suggested that N-acetylaspartate and N-acetylaspartylglutamate levels in the human brain are associated with various psychiatric disorders, including major depressive disorder. We have previously identified Shati/Nat8l, an N-acetyltransferase, in the brain using an animal model of psychosis. Shati/Nat8l synthesizes N-acetylaspartate from L-aspartate and acetyl-coenzyme A. Further, N-acetylaspartate is converted into N-acetylaspartylglutamate, a neurotransmitter for metabotropic glutamate receptor 3., Methods: Because Shati/Nat8l mRNA levels were increased in the dorsal striatum of mice following the exposure to forced swimming stress, Shati/Nat8l was overexpressed in mice by the microinjection of adeno-associated virus vectors containing Shati/Nat8l gene into the dorsal striatum (dS-Shati/Nat8l mice). The dS-Shati/Nat8l mice were further assessed using behavioral and neurochemical tests., Results: The dS-Shati/Nat8l mice exhibited behavioral despair in the forced swimming and tail suspension tests and social withdrawal in the 3-chamber social interaction test. These depression-like behaviors were attenuated by the administration of a metabotropic glutamate receptor 2/3 antagonist and a selective serotonin reuptake inhibitor. Furthermore, the metabolism of N-acetylaspartate to N-acetylaspartylglutamate was decreased in the dorsal striatum of the dS-Shati/Nat8l mice. This finding corresponded with the increased expression of glutamate carboxypeptidase II, an enzyme that metabolizes N-acetylaspartylglutamate present in the extracellular space. Extracellular serotonin levels were lower in the dorsal striatum of the dS-Shati/Nat8l and normal mice that were repeatedly administered a selective glutamate carboxypeptidase II inhibitor., Conclusions: Our findings indicate that the striatal expression of N-acetylaspartate synthetase Shati/Nat8l plays a role in major depressive disorder via the metabotropic glutamate receptor 3-mediated functional control of the serotonergic neuronal system., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Accumulating evidence suggests functional interaction between brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor (mGluR) signaling pathways in the central nervous system (CNS). To date, eight subtypes of mGluRs, mGluR1-8, have been identified, and a previous study suggested that BDNF leads to down-regulation of GluR2 mRNA in rat cerebral cortical cultures. However, precise transcriptomic effects of BDNF on other mGluRs and their cellular significance on the BDNF signaling pathway remain largely unknown. In this study, we assessed the transcriptomic effects of BDNF on mGluR1-8 in primary cultures of rat cerebral cortical neurons, and transcriptomic impacts of mGluR(s) whose expression is regulated by BDNF, on BDNF target genes. Real-time quantitative PCR (RT-qPCR) revealed that stimulation of the cultures with 100ng/mL BDNF led to marked reductions not only in the gene expression levels of mGluR2, but also in those of mGluR3, both of which belong to group II mGluRs (mGluR II). There were, on the other hand, no changes in the amounts of mGluR I (mGluR1 and 5) and III (mGluR4, 6, 7, and 8) mRNA. Further, 10ng/mL of BDNF, which mainly activates the high-affinity BDNF receptor, TrkB, but not the low-affinity receptor, p75 NTR , was able to induce down-regulation of mGluR II mRNA. The BDNF-induced suppression of mGluR II was not significantly attenuated in the presence of tetrodotoxin (TTX), a blocker for voltage-gated sodium channels. In addition, on stimulation with BDNF (100ng/mL), no significant down-regulation of mGluR II mRNA was seen in cultured astrocytes, which only express the truncated form of TrkB. Finally, we assessed the transcriptomic effect of mGluR II on the expressions of BDNF target genes, BDNF and activity-regulated cytoskeleton-associated protein (Arc). LY404039, an mGluR II agonist, enhanced the BDNF-induced up-regulation of BDNF, but not Arc. On the other hand, LY341495, an mGluR II antagonist, down-regulated BDNF mRNA levels. Collectively, these observations demonstrated the detailed functional interaction between BDNF and mGluR II: Activation of mGluR II positively regulates self-induced BDNF expression, and, in turn, BDNF negatively regulates the gene expression of mGluR II in a neuronal activity-independent manner, in cortical neurons, but not in astrocytes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The inhibitory metabotropic glutamate receptor 3 (mGluR3) plays diverse and complex roles in brain function, including synaptic plasticity and neurotransmission. We recently found that mGluR3 is downregulated in the lateral septum (LS) of postpartum females using microarray and qPCR analysis. In this study, we used double fluorescence immunohistochemical approaches to characterize mGluR3 changes in LS of the postpartum brain. The number of mGluR3-immunoractive cells was significantly reduced in the dorsal (LSD) and intermediate (LSI) but not ventral (LSV) parts of the LS in postpartum versus virgin females. mGluR3 immunoreactivity in the LS was found predominantly in neurons (~70%), with a smaller portion (~20%-30%) in astrocytes. Colocalization analysis revealed a reduced mGluR3 expression in neurons but an increased astrocytic localization in postpartum LSI. This change in the pattern of expression suggests that mGluR3 expression is shifted from neurons to astrocytes in postpartum LS, and the decrease in mGluR3 is neuron-specific. Because mGluR3 is inhibitory and negatively regulates glutamate and GABA release, decreases in neuronal expression would increase glutamate and GABA signaling. Given our recent finding that ~90% of LS neurons are GABAergic, the present data suggest that decreases in mGluR3 are a mechanism for elevated GABA in LS in the postpartum state., (© The Author(s) 2015.)

Background: While the functional disconnectivity hypothesis of schizophrenia has received considerable attention, fewer studies have investigated the contribution of genotype to structural connectivity between brain regions either in schizophrenia patients or in healthy controls. In this study, we obtained diffusion tensor imaging (DTI) data and genome-wide single nucleotide polymorphism (SNP) data from 74 cases and 87 age- and gender-matched controls., Methods: We used independent component analysis (ICA) to analyze fractional anisotropy (FA) values and correlated FA values with 121 SNPs in genes associated with myelination and/or schizophrenia risk., Results: Using ICA, we identified 6 maximally independent components in which the majority of the voxels corresponded to known white matter (WM) tracts. Among these WM-enriched components, two had FA values that were significantly decreased in patients. In addition, we examined the relationship between FA values and genotype and found that a SNP located in the intronic region of the metabotropic glutamate receptor 3 gene, GRM3, shows a significant correlation with FA values in a component containing tracts from the cortico-cerebellar-thalamic-cortical circuit of patients but not controls., Conclusions: Our findings strengthen the evidence for an association between GRM3 genotype and schizophrenia and suggest a role for glutamate neurotransmission in the establishment and maintenance of myelinated fibers., (Copyright © 2014 Elsevier B.V. All rights reserved.)