Biology subjects

Niswender, C. M.

Publications and source records attributed to Niswender, C. M..

7 recordsLinked to original sources

bioRxiv2026

CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers

The metabotropic glutamate receptor 7 (mGlu7) is an emerging therapeutic target for central nervous system disorders, but progress has been limited by a lack of selective pharmacological tools. CVN636 was recently reported as a potent and selective allosteric agonist of this receptor, capable of receptor activation in the absence of glutamate, with demonstrated efficacy in a rodent model of alcohol use disorder. Here, using complementary bioluminescence resonance energy transfer-based assays that measure both downstream signaling and G protein recruitment, we show that CVN636 does not activate the receptor on its own. Instead, CVN636 acts as a positive allosteric modulator that enhances the potency and efficacy of orthosteric agonist responses, including those of glutamate, in an agonist-dependent manner. Blockade of orthosteric agonist binding with a competitive antagonist abolished CVN636 activity, consistent with this mechanism. Furthermore, using an assay that distinguishes signaling from defined receptor dimers, we find that CVN636 activity is selective for mGlu7/7 homodimers and does not extend to any mGlu7-containing heterodimer tested. Thus, in our assay system CVN636 is an mGlu7/7 homodimer-selective positive allosteric modulator of this receptor, suggesting that its in vivo actions likely stem from action at these homomers.

pharmacology and toxicology↗

bioRxiv2026

Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlu1/5 Heterodimers

Class C GPCRs function as obligate dimers in which only one G protein can engage the complex at a time, but how each protomer contributes to heterodimer coupling has remained unresolved. Using CODA-RET, a BRET-based assay reporting direct Gq recruitment to defined, full-length receptor pairs, we show that signaling at the mGlu/ heterodimer flows predominantly through the mGlu protomer; domain-swapped chimeras localize this dominance to the transmembrane domain. The dominance generates emergent signaling: cis-acting mGlu PAMs and NAMs undergo allosteric inversion when coupling is restricted to mGlu. By contrast, the mGlu-selective NAM MTEP is silent at the heterodimer, mirroring mGlus minimal role in driving Gq. Because the mGlu PAM tested acts only in cis, a trans-acting mGlu PAM would theoretically be selective for mGlu/ homomers. These findings open a pharmacological design space in which protomer target and cis-versus-trans mode of action tune selectivity across mGlu/, mGlu/, and mGlu/ dimers.

neuroscience↗

bioRxiv2025

Reciprocal regulation of the H3 histamine receptor in Rett syndrome and MECP2 Duplication 1 syndrome: implications for therapeutic development

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded this H3 receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H3 receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H3 receptor, (R)--methylhistamine (RAMH), and the H3 receptor inverse agonist, pitolisant (Wakix(R)), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (MecpNull/+), but pitolisant had no effect on the behaviors examined here in MDS animals (MECP2Tg1).

neuroscience↗

bioRxiv2025

Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy

We have reported that levels of metabotropic glutamate receptor 7 (mGlu7) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. Additionally, we identified decreases in mGlu7 levels in Mecp2+/- female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu7 corrected deficits in cognitive, social, and respiratory domains. Here, we expanded our studies to a larger cohort of RTT samples covering a range of mutations and evaluated expression of the three widely expressed group III mGlu receptors (mGlu4,7 and 8). We found significant decreases in mGlu7, but not mGlu4 or mGlu8, mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu4 and mGlu8 in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu7 expression only in patients with mutations that induce more severe symptoms. We then administered the PAM VU0422288 to mice modeling the mild R306C mutation (Mecp2R306C/+) and found a significant reduction in apneas induced by VU0422888 administration despite no decreases in mGlu7 expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu7 PAMs in reducing apneas in RTT patients.

neuroscience↗

bioRxiv2020

Activating mGlu3 metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus.

BackgroundPolymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. MethodsWe examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. ResultsmGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through a mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. ConclusionsThese data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function - providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.

pharmacology and toxicology↗

bioRxiv2020

Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy

Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

pharmacology and toxicology↗

bioRxiv2019

Biased M1 positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for the potential improvement of cognitive function in patients suffering from Alzheimers disease and schizophrenia. M1 PAM discovery programs have produced a structurally diverse range of M1 PAMs with distinct pharmacological properties, including different levels of agonist activity and differences in signal bias. This includes the recent discovery of novel biased M1 PAMs that can potentiate coupling of M1 to activation of phospholipase C but not phospholipase D (PLD). However, little is known about the role of PLD in M1 signaling in native systems and it is not clear whether biased M1 PAMs will display differences in modulating M1-mediated responses in native tissue. We now report a series of studies using novel PLD inhibitors and PLD knockout mice to show that PLD is necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Importantly, biased M1 PAMs that do not couple to PLD not only fail to potentiate orthosteric agonist-induced LTD but also block M1-dependent LTD in the PFC. In contrast, biased and non-biased M1 PAMs act similarly in potentiating M1-dependent electrophysiological responses that are PLD-independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain CNS functions and that biased M1 PAMs function differently in brain regions implicated in cognition.\n\nSummaryWe demonstrate a novel role of phospholipase D in M1-dependent rodent cortical plasticity and M1 PAMs that do not couple to phospholipase D have functionally distinct effects on cortical plasticity than non-biased M1 PAMs.

neuroscience↗