Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Abstract

Mutations that lead to Huntington's disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M 4 subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M 4 positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M 4 PAMs could provide a therapeutic strategy for the treatment of HD.neurodegenerative | basal ganglia | movement disorder | trinucleotide repeat disorder H untington's disease (HD) is a rare and fatal neurodegenerative disease caused by an expansion of a CAG triplet repeat in Htt, the gene that encodes for the protein huntingtin (1, 2). HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3-7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6-16).Striatal spiny projection neurons (SPNs) receive large glutamatergic inputs from the cortex and thalamus, as well as dopaminergic innervation from the substantia nigra. In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17, 18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12-14) and could contribute to synaptic changes observed in later stages of HD (19,20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.Muscarinic acetylcholine receptors (mAChRs), particularly M 4 , can inhibit transmission at corticostriatal synapses (21-25). Therefore, it is possible that selective activation of specific mAChR subtypes could normalize excessive corticostriatal t...

Discovery and Development of Muscarinic Acetylcholine M₄ Activators as Promising Therapeutic Agents for CNS Diseases

“…Pancani et al reported that chronic administration of VU0467154 beginning at a pre-symptomatic age (2 months old) could prevent the appearance of deficits in both glutamatergic and dopaminergic neurotransmissions in 5 months old YAC128 mice models of Huntington's disease. 42) Motor coordination deficits and locomotor hypoactivity were also prevented by chronic treatment in YAC128 mice. Additionally, Shen et al reported that the M 4 mAChR PAM VU10010 blocks aberrant long-term potentiation in direct-pathway spiny projection neurons in an L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) mice model.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Extensive studies in rodents and non-human primates suggest that these actions of M 4 PAMs on striatal plasticity could provide therapeutic benefits in treating L-DOPA-induced dyskinesia in Parkinson's disease (Shen et al, 2016). Furthermore, M 4 PAMs can normalize excessive excitatory transmission at cortico-striatal synapses in rodent models of Huntington's disease and chronic administration of M 4 PAMs prevents the appearance of motor deficits in these animals (Pancani et al, 2015). Finally, the ability of M 4 PAMs to reduce behavioral effects of cocaine suggest that these agents may be useful for the treatment of substance abuse disorders (Dencker et al, 2012).…”

Challenges in the development of an M 4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs

“…M 4 (muscarinic acetylcholine receptor subtype 4) positive allosteric modulators (PAMs) represent an exciting therapeutic strategy to treat multiple domains of schizophrenia, 1-18 as well as other CNS disorders, 19,20 via a new molecular mechanism. 21 However, the great potenital has been hampered by limited chemical diversity centered on a 3-amino-thieno[2,3- b ]pyridine core, as in 1 - 4 , (Figure 1), which engenders steep SAR, species differences (rat versus human M 4 PAM potency, affinity/cooperativity and subtype selectivity), poor solubility, and/or low CNS penetration.…”