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Background and Purpose: Metabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally‐occurring mGlu1 mutations in rare SCA subtypes and linked symptoms to mGlu1 mutations. However, how mutations alter mGlu1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA‐associated mutation effects on mGlu1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology. Experimental Approach: Orthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+ mobilisation and inositol 1‐phosphate [IP1] accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery. Key Results: mGlu1 mutants exhibited differential impacts on mGlu1 expression, with a C‐terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss‐of‐function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain‐of‐function Y792C mutant mGlu1 displayed enhanced constitutive activity in IP1 assays, which manifested as reduced orthosteric agonist activity. The mGlu1 PAMs restored glutamate potency in iCa2+ mobilisation for loss‐of‐function mutations and mGlu1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild‐type mGlu1. Conclusion and Implications: Collectively, these data highlight distinct mechanisms by which mGlu1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu1 function in rare SCA subtypes. [ABSTRACT FROM AUTHOR]

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ‐amino‐butyric acid, arginine‐vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary‐derived adenylate cyclase‐activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin‐releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β‐adrenergic receptors in SCN and a mouse SCN‐derived immortalized cell line by immunohistochemical, immuno‐cytochemical, and pharmacological techniques. We then characterized the effects of β‐adrenergic agonists and antagonists on cAMP‐regulated element (CRE) signaling. Moreover, we investigated the interaction of β‐adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β‐blockers applied as anti‐hypertensive drugs. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6nclf mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6nclf retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6nclf retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA), could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6nclf mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6nclf retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds. [ABSTRACT FROM AUTHOR]