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Congenital Myasthenic Syndromes (CMS) are a set of genetic diseases that affect the neuromuscular transmission causing muscular weakness. The standard pharmacological treatment aims at ameliorating the myasthenic symptom by acetylcholinesterase inhibitors. Most patients respond well in the short and medium term, however, over time the beneficial effects rapidly fade, and the efficacy of the treatment diminishes. Increasing evidence shows that β 2 -adrenergic agonists can be a suitable choice for the treatment of neuromuscular disorders, including CMS, as they promote beneficial effects in the neuromuscular system. The exact mechanism on which they rely is not completely understood, although patients and animal models respond well to the treatment, especially over extended periods. Here, we report the use of the long-lasting specific β 2 -adrenergic agonist formoterol in a myasthenic mouse model (mnVAChT-KD), featuring deletion of VAChT (Vesicular Acetylcholine Transporter) specifically in the α-motoneurons. Our findings demonstrate that formoterol treatment (300 μg/kg/day; sc) for 30 days increased the neuromuscular junction area, induced skeletal muscle hypertrophy and altered fibre type composition in myasthenic mice. Interestingly, β 2 -adrenergic agonists have shown efficacy even in the absence of ACh (acetylcholine). Our data provide important evidence supporting the potential of β 2 -adrenergic agonists in treating neuromuscular disorders of pre-synaptic origin and characterized by disruptions in nerve-muscle communication, through a direct and beneficial action within the motor unit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

COVID-19 affects primarily the lung. However, several other systemic alterations, including muscle weakness, fatigue and myalgia have been reported and may contribute to the disease outcome. We hypothesize that changes in the neuromuscular system may contribute to the latter symptoms observed in COVID-19 patients. Here, we showed that C57BL/6J mice inoculated intranasally with the murine betacoronavirus hepatitis coronavirus 3 (MHV-3), a model for studying COVID-19 in BSL-2 conditions that emulates severe COVID-19, developed robust motor alterations in muscle strength and locomotor activity. The latter changes were accompanied by degeneration and loss of motoneurons that were associated with the presence of virus-like particles inside the motoneuron. At the neuromuscular junction level, there were signs of atrophy and fragmentation in synaptic elements of MHV-3-infected mice. Furthermore, there was muscle atrophy and fiber type switch with alteration in myokines levels in muscles of MHV-3-infected mice. Collectively, our results show that acute infection with a betacoronavirus leads to robust motor impairment accompanied by neuromuscular system alteration., Competing Interests: Declaration of competing interest We have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CB 1 R). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling. Male C57BL/6J mice were tested for contextual fear memory after low-, moderate-, or high-intensity shock protocols. The selective TRPV1 blockers SB366791 (1-10 nmol) and 6-I-NC (2 nmol) were infused via intra-dorsal hippocampus before the retrieval test session. The local levels of endocannabinoids and Arc and Zif268 mRNAs, involved in synaptic plasticity and memory, were quantified. First, both TRPV1 blockers reduced memory retrieval in animals exposed to moderate or high (but not low) intensity training protocols. In the second series of results, the magnitude of the freezing responses positively correlated with the hippocampal anandamide levels; TRPV1 and CB 1 R were found co-localized in this brain region; and the CB 1 R antagonist, AM251, prevented the effects of SB366791. Thus, endocannabinoid signaling possibly mediates the effects of TRPV1 blockers. Finally, inhibition of memory retrieval by TRPV1 blockers increased Arc and Zif268 mRNAs and impaired fear memory reinstatement. In conclusion, the modulation of fear memories by dorsal hippocampal TRPV1 channels may depend on the aversive stimulus intensity and occur via anandamide/CB 1 signaling. Moreover, TRPV1 blockers promote Arc and Zif268 transcription, with subsequent attenuation of aversive memory reinstatement., (Copyright © 2022. Published by Elsevier Ltd.)

The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu 5 receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu 5 receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu 5 receptor knockout (mGluR5 -/- ) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5 -/- /BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu 5 receptor has a role in brain aging. We demonstrated that mGluR5 -/- mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5 -/- /BACHD mice. In addition, ablation of mGlu 5 receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5 -/- mice induced microglia activation, evidenced by increased CD68 expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu 5 receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu 5 receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inhibition of dopamine transporter (DAT) by GBR12909 has been proposed as a pharmacological model of mania related to bipolar disorder (BD). Here we tested the hypothesis that GBR12909 injection impairs habituation and induces hyperlocomotion in mice, along with changes in cytokines and neurotrophic factors levels, as observed in BD patients. We also tested if lithium carbonate, sodium valproate and aripiprazole prevent GBR12909-induced locomotion. Male Swiss mice received GBR12909 (15 mg/kg) injections and locomotor responses were quantified in an open field. Cytokines and neurotrophic factors levels were assessed in the prefrontal cortex, striatum and hippocampus 30 min and 24 h after injections. Pre-treatments with lithium, valproate or aripiprazole were performed with single and repeated injection protocols. GBR12909 prevented motoric habituation and increased basal locomotion in habituated mice in the open field. This compound also induced changes in IL-2 and BDNF levels in prefrontal cortex; IL-2, IL-4 and IL-10 in striatum; and IL-10, IL-4, IFN-γ and NGF in hippocampus. GBR12909-induced hyperlocomotion was attenuated by lithium (12.5-100 mg/kg), but not valproate (75-300 mg/kg), and prevented by aripiprazole (0.1-10 mg/kg). Repeated injections of these drugs (twice a day for 3 days), however, failed to inhibit hyperlocomotion. The main limitations of the protocols in this study are the analysis of locomotion as the only behavioral parameter, changes in immune factors that may overlap with other psychiatric disorders and the lack chronic drug injections. Despite of these limitations, this study adds to previous literature suggesting DAT inhibition as a potential animal model of mania related to BD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent studies have implicated adiponectin and other adipocytokines in brain function, particularly in processes related to memory and cognition. Blood levels of adiponectin are reduced in patients with primary cognitive disorders, such as Alzheimer's disease and mild cognitive impairment, and in adult patients with major depression. The aim of the present study is to determine serum levels of adiponectin in a sample of elderly patients with major depressive disorder (MDD) as compared to healthy older adults, and to examine the correlations between adiponectin levels and parameters indicative of mood and cognitive state. We recruited fifty-one unmedicated outpatients with late-life depression (LLD) and 47 age-matched controls in this study. The diagnosis of MDD was made according to the DSM-IV criteria, and the severity of depressive episode was determined with the 21-item Hamilton Depression Scale (HDRS). Cognitive state was ascertained with the Cambridge Cognitive Test (CAMCOG) and the Mini-Mental State Examination (MMSE). Serum concentrations of adiponectin were determined using a sandwich ELISA method. Serum levels of adiponectin were significantly reduced in individuals with LLD (F = p < 0.001). Adiponectin level remained significantly reduced in after controlling for BMI index, scores on the CAMCOG, MMSE and HDRS and educational level (p < 0.001). Adiponectin levels showed a negative correlation with HDRS scores (r = -0.59, p < 0.001) and BMI index (r = -0.42, p < 0.001); and showed a positive correlation with CAMCOG (r = 0.34, p < 0.01) and MMSE scores (r = 0.20, p = 0.05). The availability of circulating adiponectin is reduced in older adults with major depression, with likely implications on cognitive and mood state. Additional studies are required to determine whether this abnormality pertains to the pathophysiology of geriatric depression per se, or is a consequence of the morbid state., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The Glial cell-line derived neurotrophic factor (GDNF) is part of the TGF-β superfamily and is abundantly expressed in the central nervous system. Changes in GDNF homeostasis have been reported in affective disorders., Aim: To assess serum GDNF concentration in elderly subjects with late-life depression, before antidepressant treatment, as compared to healthy elderly controls., Methods: Thirty-four elderly subjects with major depression and 37 age and gender-matched healthy elderly controls were included in this study. Diagnosis of major depression was ascertained by the SCID interview for DSM-IV and the severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HDRS-21). Serum GDNF concentration were determined by sandwich ELISA., Results: Patients with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 scores (r = -0.343, p = 0.003)., Discussion: Our data provide evidence that GDNF may be a state marker of depressive episode in older adults. Changes in the homeostatic control of GDNF production may be a target to development of new antidepressant strategies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)