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Sleep-wake-related changes in intracellular chloride regulate plasticity at glutamatergic cortical synapses.
Wakefulness and sleep affect the brain's ability to exhibit plastic changes.1,2 For instance, the potentiation of cortical excitatory synaptic connections is associated with the active period, when animals are mainly awake.3,4,5,6,7 It is unclear, however, how changes in neuronal physiology that are associated…
Unique pathways downstream of TLR-4 and TLR-7 activation: sex-dependent behavioural, cytokine, and metabolic consequences.
INTRODUCTION: Post-infection syndromes are characterised by fatigue, muscle pain, anhedonia, and cognitive impairment; mechanistic studies exploring these syndromes have focussed on pathways downstream of Toll-like receptor (TLR) 4 activation. Here, we investigated the mechanistic interplay between…
TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders.
The lysosomal two-pore channel 2 (TPC2) modulates intracellular calcium (Ca2 +) signaling and has been implicated in inflammatory, cardiovascular, and neurodegenerative conditions, as well as cancer and viral infections. Despite its potential as a drug target, TPC2 is still in the early stages of therapeutic dev…
Glucokinase activity in diabetes: too much of a good thing?
Type 2 diabetes (T2D) is a global health problem characterised by chronic hyperglycaemia due to inadequate insulin secretion. Because glucose must be metabolised to stimulate insulin release it was initially argued that drugs that stimulate glucokinase (the first enzyme in glucose metabolism) would enhanc…
Period3 modulates the NAD+-SIRT3 axis to alleviate depression-like behaviour by enhancing NAMPT activity in mice.
INTRODUCTION: PER3 deficiency is associated with depression-like behaviors, but the underlying mechanisms remain unclear. OBJECTIVES: This study aims to elucidate the role and mechanism of PER3 in regulating depression-like behaviors in mice. METHODS: Depression-like behaviors were assessed using the su…
The role of electroencephalography in epilepsy research-From seizures to interictal activity and comorbidities.
Electroencephalography (EEG) has been instrumental in epilepsy research for the past century, both for basic and translational studies. Its contributions have advanced our understanding of epilepsy, shedding light on the pathophysiology and functional organization of epileptic networks, and the mechanisms und…
More and Less Fear in Serotonin Transporter Knockout Mice.
Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define…
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…