A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

The metabotropic glutamate receptor 7 (mGlu7) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7–global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population

An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia

Descripción de ciperáceas y gramíneas de Tierra del Fuego.Facultad de Ciencias Naturales y Muse

PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems

Positive allosteric modulators (PAMs) of the M₁ subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer’s disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M₁ PAMs may reduce efficacy and contribute to adverse effect liability. However, the M₁ PAM PF-06827443 was reported to have only weak agonist activity at human M₁ receptors but produced M₁-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M₁ and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems

Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu₁), Based on an <i>N</i>‑(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu₁ Receptors Found in Schizophrenics

The therapeutic potential of selective mGlu₁ activation is vastly unexplored relative to the other group I mGlu receptor, mGlu₅; therefore, our lab has focused considerable effort toward developing mGlu₁ positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu₁ PAMs based on an <i>N</i>-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)­phenyl)-3-methylfuran-2-carboxamide scaffold provided <b>17e</b>, a potent (mGlu₁ EC₅₀ = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (<i>K</i>_p) of 1.02) mGlu₁ PAM tool compound, that potentiated not only wild-type human mGlu₁ but also mutant mGlu₁ receptors derived from deleterious <i>GRM1</i> mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu₁ ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu₅ ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window