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Synaptic Targets and Cellular Sources of CB1 Cannabinoid Receptor and Vesicular Glutamate Transporter-3 Expressing Nerve Terminals in Relation to GABAergic Neurons in the Human Cerebral Cortex.
Cannabinoid receptor 1 (CB1) regulates synaptic transmission through presynaptic receptors in nerve terminals, and its physiological roles are of clinical relevance. The cellular sources and synaptic targets of CB1-expressing terminals in the human cerebral cortex are undefined. We demonstrate a variable l…
Lipid-Modulated, Graduated Inhibition of N-Glycosylation Pathway Priming Suggests Wide Tolerance of ER Proteostasis to Stress.
Protein N-glycosylation is a cotranslational modification that takes place in the endoplasmic reticulum (ER). Disruption of this process can result in accumulation of misfolded proteins, known as ER stress. In response, the unfolded protein response (UPR) restores proteostasis or responds by controlling…
Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites.
Voltage-gated sodium channel α-subunits (NaV1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The NaV β-subunits (β1-4) have been shown to modulate α-subunit properties. Homo-oligomerization of β-subunits on neighboring or opposing plasma membranes has been suggested to f…
New insights into the genetic etiology of Alzheimer's disease and related dementias.
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD…
Ex-Vivo 13C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.
Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric a…
Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression.
INTRODUCTION: Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. METHODS: We employed the…
Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness.
BACKGROUND: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infe…
Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease.
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS an…
Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function.
BACKGROUND AND PURPOSE: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allost…
Impact of masticatory activity and rehabilitation on astrocyte morphology across the molecular layer of the dentate gyrus: Insights from the outer, medial, and inner sublayers and their relationship with spatial learning and memory.
The dentate gyrus plays a crucial role in learning and spatial memory, particularly in its middle third molecular layer, which receives the primary afferent input via the medial perforant path. Interestingly, changes in masticatory activity are described to affect this region with visible astrogliosis, release of pro-i…
Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I.
BACKGROUND AND AIMS: Atherosclerotic cardiovascular diseases are the leading cause of death. Apolipoprotein A-I (apoA-I) mediates cholesterol efflux to lower the risks of atherosclerosis. Elevating circulating apoA-I is an effective strategy for atheroprotection. However, the regulatory mechanisms of apoA-I…
Pramipexole for the Treatment of Depression: Efficacy and Mechanisms.
Dopaminergic mechanisms are a plausible treatment target for patients with clinical depression but are relatively underexplored in conventional antidepressant medications. There is continuing interest in the potential antidepressant effects of the dopamine receptor agonist, pramipexole, with data fr…
Diaphragm relaxation causes seizure-related apnoeas in chronic and acute seizure models in rats.
Ictal central apnoea is a feature of focal temporal seizures. It is implicated as a risk factor for sudden unexpected death in epilepsy (SUDEP). Here we study seizure-related apnoeas in two different models of experimental seizures, one chronic and one acute, in adult genetically-unmodified rats, to determine me…