Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders

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. They have shown great promise as drug targets for numerous neurological and psychiatric diseases. Moreover, the development of subtype-selective allosteric modulators has allowed detailed studies of each receptor subtype. Here, we focus on the metabotropic glutamate receptor 7 (mGlu7) as a potential therapeutic target for NDDs. mGlu7 is expressed widely throughout the brain in regions that correspond to the symptom domains listed above and has established roles in synaptic physiology and behavior. Single nucleotide polymorphisms and mutations in the GRM7 gene have been associated with idiopathic autism and other NDDs in patients. In rodent models, existing literature suggests that decreased mGlu7 expression and/or function may lead to symptoms that overlap with those of NDDs. Furthermore, potentiation of mGlu7 activity has shown efficacy in a mouse model of Rett syndrome. In this review, we summarize current findings that provide rationale for the continued development of mGlu7 modulators as potential therapeutics

Cell-Type Specific Expression of a Dominant Negative PKA Mutation in Mice

We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology

Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC(50) = 650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR

Phenotypes Observed by Activating the RIαB Allele with Various Cre Driver Mouse Lines.

<p>Phenotypes Observed by Activating the RIαB Allele with Various Cre Driver Mouse Lines.</p

RIαB/Alb-<i>cre</i> mice exhibit increases in glucose disposal.

<p><i>A</i>, Blood glucose levels were determined in 24 hr fasted WT, RIαB, and RIαB/Alb-<i>cre</i> mice. n = 10. <i>B</i>, Glucose tolerance test was performed in 24 hr fasted WT, RIαB, and RIαB/Alb-<i>cre</i> mice injected i.p. with 2 mg of glucose per gram of body weight. Blood glucose levels were determined at the indicated time points. Over the first 60 min, the glucose disposal of RIαB/Alb-cre was significantly enhanced compared to RIαB alone (p<.001). n = 7. <i>C</i>, WT, RIαB, and RIαB/Alb-<i>cre</i> mice were injected with 0.75 mU of insulin per kilogram of body weight at time 0 and blood glucose levels were determined at the indicated time points. Values are presented as means ± SEM. n = 10.</p