Abstract:Neurodevelopmental disorders (NDDs) are characterized by a wide range of symptoms including delayed speech, intellectual disability, motor dysfunction, social deficits, breathing problems, structural abnormalities, and epilepsy. Unfortunately, current treatment strategies are limited and innovative new approaches are sorely needed to address these complex diseases. The metabotropic glutamate receptors are a class of G protein-coupled receptors that act to modulate neurotransmission across many brain structures… Show more
“…Additionally, there are ample neuropharmacological studies focusing on the potential for using allosteric modulators of mGluRs in the treatment of neurological diseases and epilepsy 52,53 . Selective positive allosteric modulators (PAMs) for group III mGluRs have been recently developed, potentially representing novel targeted and personalized therapy in partial mGluR7 LoF (hypomorph alleles).…”
Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
“…Additionally, there are ample neuropharmacological studies focusing on the potential for using allosteric modulators of mGluRs in the treatment of neurological diseases and epilepsy 52,53 . Selective positive allosteric modulators (PAMs) for group III mGluRs have been recently developed, potentially representing novel targeted and personalized therapy in partial mGluR7 LoF (hypomorph alleles).…”
Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
“…PLAUSIBILITY OF MCFA-GPR84 DE-ORPHANIZATION 1927 serving to inhibit further glutamate release (Fisher et al, 2018). Likewise, a recently deorphanized example is the HCA 2 receptor that has a 700 mM affinity for b-hydroxybutyrate, which reaches these levels during fasting or ketogenesis, and then acts to prevent further lipolysis (Offermanns and Schwaninger, 2015).…”
GPR84 is an inflammation-induced receptor highly expressed on immune cells, yet its endogenous ligand is still unknown. This makes any interpretation of its physiological activity in vivo difficult. However, experiments with potent synthetic agonists have highlighted what the receptor can do, namely, enhance proinflammatory signaling and macrophage effector functions such as phagocytosis. Developing drugs to block these effects has attracted interest from the scientific community with the aim of decreasing disease activity in inflammatory disorders or enhancing inflammation resolution. In this review, we critically reassess the widely held belief that the major role of GPR84 is that of being a medium-chain fatty acid (MCFA) receptor. While MCFAs have been shown to activate GPR84, it remains to be demonstrated that they are present in relevant tissues at appropriate concentrations. In contrast to four other ''full-time'' free fatty acid receptor subtypes, GPR84 is not expressed by enteroendocrine cells and has limited expression in the gastrointestinal tract. Across multiple tissues and cell types, the highest expression levels of GPR84 are observed hours after exposure to an inflammatory stimulus. These factors obscure the relationship between ligand and receptor in the human body and do not support the exclusive physiological pairing of MCFAs with GPR84. To maximize the chances of developing efficacious drugs for inflammatory diseases, we must advance our understanding of GPR84 and what it does in vivo.
“…The relationship between mGlu 7 and memory is also complex, with the mGlu 7 -negative modulator MMPIP both impairing NOD in normal mice [58] and recently proposed as a putative antipsychotic due to its ability to reverse acute MK-801-induced hyperactivity and cognitive deficits in mouse NOD and rat spatial delayed alternation tests [56]. It has been suggested mGlu 7 may represent a new treatment target for neurodevelopmental disorders [134], and current neurochemical and behavioral findings certainly appear to justify continued preclinical evaluation of mGlu 7 allosteric antagonists against a broader variety of PCP-Iso-induced cognitive impairments. This is important since the NOD test of visual recognition memory performed here has translational relevance to only one of several cognitive domains impaired in schizophrenia [45].…”
Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates "dual-hit" neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal-and drugevoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT 6 antagonistevoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT 6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu 7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT 6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT 6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT 6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu 7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.
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