Targeting the M4 muscarinic acetylcholine receptor in neurodegenerative disease

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Studentship strategic priority area:Basic and Clinical ResearchKeyword:Alzheimer's disease, neurodegeneration, muscarinic, GPCRThis studentship will combine chemical genetics, transgenic mouse models, models of neurodegenerative disease and unique chemical probes to define the impact of selectively targeting M4 muscarinic acetylcholine receptors (M4 mAChRs) in neurodegenerative disease. In collaboration with Eli Lilly, we have developed a mouse model of neurodegeneration (murine prion disease) in which we can directly probe the impact of targeting muscarinic receptors in a disease context. These prion-infected mice show accumulation of misfolded prion protein (PrPsc), astrogliosis and synaptic dysfunction and undergo progressive neuronal loss which ultimately reaches end-stage clinical disease. Furthermore, prion-diseased mice display significant cholinergic dysfunction with associated memory deficits. This memory-deficit can completely restored by treatment with xanomeline, an M1/M4 clinically validated muscarinic agonist, and also by highly selective M1 mAChR positive allosteric modulators (PAMs). We know therefore that M1 mAChRs can have an impact on prion neurodegeneration - what we do not know is how important the M4 mAChR is in neurodegeneration. This PhD programme will use unique chemical tools made available through Eli Lilly, together with chemical genetic animal models, to probe the role of the M4 mAChR in neurodegeneration. Specifically we will:. Employ a novel chemical genetic mouse model in which the wild type gene locus encoding the M4 mAChR has been replaced by a coding sequence that expresses a mutant form of this receptor that is unable to be activated by the endogenous ligand, acetylcholine, but only by the synthetic ligand, clozapine-N-oxide (CNO). This mutant receptor, called Designer Receptor Exclusively Activated by Designer Drug (DREADD), allows us to specifically probe the physiological function of M4 mAChRs since we can monitor the behavioural response following stimulation of the M4-mutant receptors with CNO. Using this mouse model we can induce prion-neurodegeneration and investigate the effects of selective M4-mAChR stimulation with an orthosteric agonist on cognitive decline in a neurodegenerative setting.. An alternative to the chemical genetic approach above is to employ our unparalleled access to an array of novel M4 mAChR ligands (including orthosteric and allosteric), through Eli Lilly, to test the possibility that pharmacological targeting this receptor may rescue impairments in learning and memory in prion-infected mice.. In addition to investigating effects on learning and memory deficits, we will test of the impact of novel M4 mAChR ligands on the progression of neurodegenerative disease, particularly to explore the impact of novel muscarinic ligands on the survival of prion-diseased mice. Amongst other hallmarks of disease, we will probe the effects of M4 mAChR activation on synaptic dysfunction, neuronal loss and aggregation of misfolded proteins