Key pointsr Millions of elderly individuals have dysphagia, a debilitating and life-threatening condition in which the ability to swallow is impaired.r Several muscles surround the three regions of the pharynx, which are essential for proper swallowing, yet the effects of ageing and disease on these muscles are not well understood.r We demonstrate that the fibre size of murine pharyngeal muscles is differentially affected by ageing and muscular dystrophy depending on their location within the pharynx.r Using a mouse model of an age-associated dysphagic disease (oculopharyngeal muscular dystrophy), we show that overexpression of wild-type polyadenylate binding nuclear protein 1 in muscle tissue prevents age-related dysphagia and age-related muscle atrophy of laryngopharyngeal muscles.r These results demonstrate that mice are an excellent model for studying mechanisms of ageing and disease on pharyngeal muscle physiology, and such studies could lead to new therapies for individuals with dysphagia.Abstract The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia. Abbreviations A10-WT, wild-type A10.1 PABPN1 overexpression transgenic mouse; A17-MUT, mutant A17.1 PABPN1 overexpression transgenic mouse; FVB, Friend leukaemia virus B; H&E, haematoxylin and eosin; MHC, myosin heavy chains; OPMD, oculopharyngeal muscular dystrophy; PABPN1, polyadenylate binding nuclear protein 1; type I, slow twitch oxidative myofibre; type II, fast twitch glycolytic myofibre; WT, wild-type.

Degeneration of dopaminergic (DA) neurons is a hallmark of Parkinson’s disease (PD). The mechanism involved in the site‐specific dysfunction of DA in the substantia nigra pars compacta (SNpc) but not in the ventral tegmental area (VTA) is not well understood. Glycogen Synthase Kinase 3 beta (GSK3β) activity has been shown to be increased in mouse models of PD and implicated in the human disease. Here we use the rotarod test to evaluate locomotion and balance, the open field test to evaluate anxiety and locomotion and whole cell current studies of DA neurons in brain slices of the midbrain to test the hypothesis that increased GSK3β activity in a mouse model for rapidly progressive PD inhibits A‐Type K+ channel activity specifically in the SNpc compared with the VTA, resulting in motor and non‐motor dysfunction in these mice. Using mice that overexpress A53Tα‐synuclein (A53T) under the pituitary specific PITX3 promoter as an animal model for PD, which developed gait disturbances as early as 7 weeks of age, we determined that A53T mice demonstrated decreased rotarod time compared with controls (134.4±27.0 sec (n=15) vs 287.1±13.0 sec (n=30); p < 0.001). Furthermore, treatment for 3 weeks with a GSK3β inhibitor, TWS‐119, resulted in an increase in rotarod time after 1 week (2.4±0.55 fold (n=5); p = 0.043), which was stable for up to 3 weeks. Furthermore, the open field test demonstrated that A53T mice spent more time in the periphery and traveled less in the center as compared to control mice (78.6±16.3 cm (n=17) vs 177.8±24.0 cm (n=30); p=0.006), and treatment with TWS‐119 led to a decrease in time spent in the periphery and an increase in distance traveled in the center as compared to control, indicating that GSK3β inhibition improved motor and non‐motor functions in this model. Whole‐cell patch‐clamp recordings of DA neurons from brain slices of A53T mice demonstrated a nearly 2‐fold increase in the incidence of spontaneous firing of DA neurons in the SNpc in response to current injection compared to WT (34.8±5.5 pA (n=14) vs 16±5.4 pA (n=6); p=0.04), while firing of DA neurons in slices from TWS‐119 treated A53T mice was not significantly different from WT. There was no difference in firing frequency in DA neurons in the VTA from brain slices from WT and A53T mice. Measurements of A‐Type K+ currents in SNpc of brain slices of A53T mice demonstrated a marked decrease in current density compared to WT (87.4±14.0pA (n=8) vs 164.7±32.4pA (n=19); p<0.001), while A‐Type currents in brain slices from TWS‐119 treated mice were not significantly different from control. Moreover, we identified a putative target site of GSK3β in the Kv4.2 structural subunits of the A‐Type K+ channel. These data support the conclusion that hyperactivity of GSK3β might play a role in the development of a PD behavioral phenotype in the PITX3/A53T mouse model for PD by mediating an increase in excitability of DA neurons via inhibition of the A‐type K channel repolarizing current specifically in DA neurons of the SNpc. This suggests the A‐Type ...