BACKGROUND: Traumatic brain injury (TBI) is a complex pathophysiological process, and increasing attention has been paid to the important role of post-synaptic density (PSD) proteins, such as glutamate receptors. Our previous study showed that a PSD protein Arc/Arg3.1 (Arc) regulates endoplasmic reticulum (ER) stress and neuronal necroptosis in traumatic injury in vitro.
OBJECTIVE: In this study, we investigated the expression, regulation and biological function of Arc in both in vivo and in vitro experimental TBI models.
RESULTS: Traumatic neuronal injury (TNI) induced a temporal upregulation of Arc in cortical neurons, while TBI resulted in sustained increase in Arc expression up to 24 h in rats. The increased expression of Arc was mediated by the activity of metabotropic glutamate receptor 5 (mGluR5), but not dependent on the intracellular calcium (Ca2+) release. By using inhibitors and antagonists, we found that TNI regulates Arc expression via Gq protein and protein turnover. In addition, overexpression of Arc protects against TBI-induced neuronal injury and motor dysfunction both in vivo and in vitro, whereas the long-term cognitive function was not altered. To determine the role of Arc in mGluR5-induced protection, lentivirus-mediated short hairpin RNA (shRNA) transfection was performed to knockdown Arc expression. The mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG)-induced protection against TBI was partially prevented by Arc knockdown. Furthermore, the CHPG-induced attenuation of Ca2+ influx after TNI was dependent on Arc activation and followed regulation of AMPAR subunits. The results of Co-IP and Ca2+ imaging showed that the Arc-Homer1 interaction contributes to the CHPG-induced regulation of intracellular Ca2+ release.
CONCLUSIONS: In summary, the present data indicate that the mGluR5-mediated Arc activation is a protective mechanism that attenuates neurotoxicity following TBI through the regulation of intracellular Ca2+ hemostasis. The AMPAR-associated Ca2+ influx and ER Ca2+ release induced by Homer1-IP3R pathway might be involved in this protection.

Potentiation of metabotropic glutamate receptor subtype 5 (mGluR5) function produces antipsychotic-like and pro-cognitive effects in animal models of schizophrenia and can reverse cognitive deficits induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists. However, it is currently unknown if mGluR5 positive allosteric modulators (PAMs) can modulate NMDAR antagonist-induced alterations in extracellular glutamate levels in regions underlying these cognitive and behavioral effects, such as the medial prefrontal cortex (mPFC). We therefore assessed the ability of the mGluR5 PAM, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), to reduce elevated extracellular glutamate levels induced by the NMDAR antagonist, dizocilpine (MK-801), in the mPFC. Male Sprague-Dawley rats were implanted with a guide cannula aimed at the mPFC and treated for ten consecutive days with MK-801 and CDPPB or their corresponding vehicles. CDPPB or vehicle was administered thirty minutes before MK-801 or vehicle each day. On the final day of treatment, in vivo microdialysis was performed, and samples were collected every thirty minutes to analyze extracellular glutamate levels. Compared to animals receiving only vehicle, administration of MK-801 alone significantly increased extracellular levels of glutamate in the mPFC. This effect was not observed in animals administered CDPPB before MK-801, nor in those administered CDPPB alone, indicating that CDPPB decreased extracellular glutamate release stimulated by MK-801. Results indicate that CDPPB attenuates MK-801 induced elevations in extracellular glutamate in the mPFC. This effect of CDPPB may underlie neurochemical adaptations associated with the pro-cognitive effects of mGluR5 PAMs in rodent models of schizophrenia.

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin-Reed-Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation.

BACKGROUND: Clinical evidence suggests that Esketamine (ESK) is an effective treatment for depression. However, the effects of Esketamine in treating depression-like behavior induced by neuropathic pain is unclear. The underlying molecular mechanisms require further investigation to provide new therapeutic targets for the treatment of clinical neuropathic pain-related depression.
METHODS: A neuropathic pain-related depression model was established in rats with spared nerve injury (SNI). Male Sprague-Dawley rats were randomly divided into four groups: Sham Group, SNI group, SNI + Normal Saline (NS) Group and SNI + ESK5mg/kg Group. Mechanical pain thresholds were measured to assess pain sensitivity in SNI rats. On the 14th day after surgery a forced swim test and sucrose preference test were used to evaluate the depressive-like behavior of rats in each group. Further, a proteomic analysis was used to quantify differentially expressed proteins. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to explore the main protein targets of SNI in the medial prefrontal cortex. The expression of proteins was detected by Western blotting.
RESULTS: A neuropathic pain-related depression model was established. Compared with the Sham group, the mechanical pain threshold was decreased significantly (13.2 ± 1.0 vs. 0.7 ± 0.01 g n = 8), while immobility on the forced swim test was also decreased (93.1 ± 7.4 vs. 169.5 ± 9.6 s n = 8), and sucrose preference rate was significantly increased (98.8 ± 0.3 vs. 73.1 ± 1.4n = 7) in SNI group rats. Compared with the SNI + NS group, the mechanical pain threshold was not statistically significant, while immobility on the forced swim test was clearly decreased (161.1 ± 11.6 vs. 77.9 ± 5.0 s n = 8), and sucrose preference rate was significantly increased (53.1 ± 8.9 vs. 96.1 ± 1.4n = 7) in SNI + ESK5mg/kg group rats. To further investigate the underlying mechanism, we employed proteomics to identify proteins exhibiting more than a 1.2-fold difference (P < 0.05) in expression levels within each group for subsequent analysis. Relative to the Sham group, 88 downregulated and 104 up-regulated proteins were identified in the SNI group, while 120 and 84 proteins were up- and down-regulated in the Esketamine treatment group compared with the SNI + NS group. Compared with Sham group, the expressions of mGluR5 and Homer1a were up-regulated in the medial prefrontal cortex (mPFC) in SNI group (mGluR5:0.97 ± 0.05 vs 1.47 ± 0.15, Homer1a:1.03 ± 0.06 vs 1.46 ± 0.16n = 6), and down-regulated after intervention with Esketamine (mGluR5:1.54 ± 0.11 vs 1.06 ± 0.07, Homer1a:1.51 ± 0.13 vs 1.12 ± 0.34n = 6).
CONCLUSIONS: Low-dose Esketamine appeared to relieve depression-like behavior induced by neuropathic pain. The Homer1a-mGluR5 signaling pathway might be the mechanism of antidepressant effect of Esketamine.

暂无摘要。

UNASSIGNED: Gender incongruence (GI) is characterized by a marked incongruence between an individual\'s experienced/expressed gender and the assigned sex at birth. It includes strong displeasure about his or her sexual anatomy and secondary sex characteristics. In some people, this condition produces a strong distress with anxiety and depression named gender dysphoria (GD). This condition appears to be associated with genetic, epigenetics, hormonal as well as social factors. Given that L-glutamate is the major excitatory neurotransmitter in the central nervous system, also associated with male sexual behavior as well as depression, we aimed to determine whether metabotropic glutamate receptors are involved in GD.
UNASSIGNED: We analyzed 74 single nucleotide polymorphisms located at the metabotropic glutamate receptors (mGluR1, mGluR3, mGluR4, mGluR5, mGluR7 and mGluR8) in 94 transgender versus 94 cisgender people. The allele and genotype frequencies were analyzed by c2 test contrasting male and female cisgender and transgender populations. The strength of the associations was measured by binary logistic regression, estimating the odds ratio (OR) for each genotype. Measurement of linkage disequilibrium, and subsequent measurement of haplotype frequencies were also performed considering three levels of significance: P ≤ 0.05, P ≤ 0.005 and P ≤ 0.0005. Furthermore, false positives were controlled with the Bonferroni correction (P ≤ 0.05/74 = 0.00067).
UNASSIGNED: After analysis of allele and genotypic frequencies, we found twenty-five polymorphisms with significant differences at level P ≤ 0.05, five at P ≤ 0.005 and two at P ≤ 0.0005. Furthermore, the only two polymorphisms (rs9838094 and rs1818033) that passed the Bonferroni correction were both related to the metabotropic glutamate receptor 7 (mGluR7) and showed significant differences for multiple patterns of inheritance. Moreover, the haplotype T/G [OR=0.34 (0.19-0.62); P<0.0004] had a lower representation in the transgender population than in the cisgender population, with no evidence of sex cross-interaction.
UNASSIGNED: We provide genetic evidence that the mGluR7, and therefore glutamatergic neurotransmission, may be involved in GI and GD.

Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [3H]raclopride on dopamine D2/3 receptors, [3H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [3H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [3H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [3H]UCB-J and [3H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.

OBJECTIVE: Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis-dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor-mediated long-term depression (G1-mGluR-LTD) following seizures.
METHODS: We used a knock-in mice line that express ArcKR and two hyperexcitation models: an in vitro model, where hippocampal slices were exposed to zero Mg2+, 6 mM K+; and an in vivo model, where kainic acid was injected unilaterally into the hippocampus. In both models, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 region of hippocampal slices in response to Schaffer collateral stimulation and G1-mGluR-LTD was induced chemically with the group 1 mGluR agonist DHPG.
RESULTS: In the in vitro model, ArcKR expression enhanced the effects of seizure activity and increased the magnitude of G1-mGluR LTD, an effect that could be blocked with the mGluR5 antagonist MTEP. In the in vivo model, fEPSPs were significantly smaller in slices from ArcKR mice and were less contaminated by population spikes. In this model, the amount of G1-mGluR-LTD was significantly less in epileptic slices from ArcKR mice as compared to wildtype (WT) mice.
CONCLUSIONS: We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model.

 Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer\'s disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of \"eat-me\" signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research.

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.