Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia.

Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood.

Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) contribute to vascular cognitive impairment and dementia (VCID), with aging and hypertension being key risk factors. Mitochondrial oxidative stress is a hallmark of cerebrovascular aging, leading to endothelial dysfunction. This study tests the hypothesis that increased mitochondrial oxidative stress contributes to age-related CMH susceptibility and evaluates the mitochondrial-targeted antioxidative peptide SS-31 (elamipretide) as a potential protective agent in an aged, hypertensive mouse model.

Senescent Endothelial Cells in Cerebral Microcirculation Are Key Drivers of Age-Related Blood-Brain Barrier Disruption, Microvascular Rarefaction, and Neurovascular Coupling Impairment in Mice.

With advancing age, neurovascular dysfunction manifests as impaired neurovascular coupling (NVC), microvascular rarefaction, and blood-brain barrier (BBB) disruption, contributing to vascular cognitive impairment (VCI). Our previous research established a causal link between vascular senescence induced cerebromicrovascular dysfunction and cognitive decline in accelerated aging models. The present study examines whether chronological aging promotes endothelial senescence, adversely affecting neurovascular health, and whether senolytic therapies can enhance neurovascular function and cognitive performance in aged mice.

Chronic β3 adrenergic agonist treatment improves neurovascular coupling responses, attenuates blood-brain barrier leakage and neuroinflammation, and enhances cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction.

Robust GRK2/3/6-dependent desensitization of oxytocin receptor in neurons.

Oxytocin plays critical roles in the brain as a neuromodulator, regulating social and other affective behavior. However, the regulatory mechanisms controlling oxytocin receptor (OXTR) signaling in neurons remain unexplored. In this study, we have identified robust and rapid-onset desensitization of OXTR response in multiple regions of the mouse brain.

Synapse-Specific Defects in Synaptic Transmission in the Cerebellum of W246G Mutant ELOVL4 Rats-a Model of Human SCA34.

Elongation of very long fatty acids-4 (ELOVL4) mediates biosynthesis of very long chain-fatty acids (VLC-FA; ≥28 carbons). Various mutations in this enzyme result in spinocerebellar ataxia-34 (SCA34). We generated a rat model of human SCA34 by knock-in of a naturally occurring c.

The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.

Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase.

Selective Ablation of in Astrocytes Induces Sex-Specific Effects on Cognitive Function, d-Serine Availability, and Astrogliosis.

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer's disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age.

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34.

Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by ataxia and cerebellar atrophy. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is caused by mutations in ELOVL4 (ELOngation of Very Long-chain fatty acids 4), a fatty acid elongase essential for biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp.

Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Aβ-Induced Changes in Neural Activity.

Homeostatic synaptic plasticity (HSP) is the ability of neurons to exert compensatory changes in response to altered neural activity. How pathologically induced activity changes are intertwined with HSP mechanisms is unclear. We show that, in cholinergic neurons from Drosophila, beta-amyloid (Aβ) peptides Aβ40 and Aβ42 both induce an increase in spontaneous activity.

The flavonoid, 2'-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia.

Tonic inhibitory currents, mediated by extrasynaptic GABA receptors, are elevated at a delay following stroke. Flavonoids minimise the extent of cellular damage following stroke, but little is known about their mode of action. We demonstrate that the flavonoid, 2'-methoxy-6-methylflavone (0.

Enhanced synaptic inhibition in the cerebellar cortex of the ataxic PMCA2(-/-) knockout mouse.

Mice with genetic deletion of a calcium extrusion pump, the plasma membrane calcium ATPase isoform 2, PMCA2, exhibit overt cerebellar ataxia, but the cellular mechanisms are only partially understood. Here, we report an enhanced synaptic GABAergic inhibition within the molecular layer of cerebellar cortex slices from PMCA2 knockout (PMCA2(-/-)) mice, a finding that could contribute to the observed ataxia. Purkinje neurons from PMCA2(-/-) mice exhibited an increased frequency and amplitude of spontaneous inhibitory post-synaptic currents that was accompanied by an enhanced spontaneous firing frequency of molecular layer interneurons (both basket cells and stellate cells).

Contribution of plasma membrane Ca ATPase to cerebellar synapse function.

The cerebellum expresses one of the highest levels of the plasma membrane Ca(2+) ATPase, isoform 2 in the mammalian brain. This highly efficient plasma membrane calcium transporter protein is enriched within the main output neurons of the cerebellar cortex; i.e.

Reduced expression of the Ca(2+) transporter protein PMCA2 slows Ca(2+) dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination.

Cerebellar Purkinje neurones (PNs) express high levels of the plasma membrane calcium ATPase, PMCA2, a transporter protein critical for the clearance of calcium from excitable cells. Genetic deletion of one PMCA2 encoding gene in heterozygous PMCA2 knock-out (PMCA2(+/-) mice enabled us to determine how PMCA2 influences PN calcium regulation without the complication of the severe morphological changes associated with complete PMCA2 knock-out (PMCA2(-/-) in these cells. The PMCA2(+/-) cerebellum expressed half the normal levels of PMCA2 and this nearly doubled the time taken for PN dendritic calcium transients to recover (mean fast and slow recovery times increased from 70 ms to 110 ms and from 600 ms to 1100 ms).

betaCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses.

We found that betaCaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation.

Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation.

Endocannabinoid signaling has been demonstrated to mediate depolarization-induced suppression of excitation at climbing fiber (CF) and parallel fiber (PF) synapses onto cerebellar Purkinje cells. Here, we show that CF-evoked release of cannabinoids (CBs) additionally suppresses a presynaptic form of long-term potentiation (LTP) at PF synapses. PF-LTP can be induced by 8 Hz PF tetanization but is blocked when the PF tetanization is paired with 4 or 1 Hz CF coactivation.

Repeated administration of group I mGluR antagonists prevents seizure-induced long-term aberrations in hippocampal synaptic plasticity.

Kindling induced by repeated application of the convulsant pentylenetetrazole (PTZ) is a validated model of epilepsy and epilepsy-related neuromorphological, neurophysiological and behavioural alterations. In this study, we examined whether kindling-induced long-term aberrations in hippocampal synaptic plasticity can be prevented by application of group I mGluR antagonists. Kindling resulted in a higher magnitude of long-term potentiation (LTP) induced by a strong high-frequency stimulation in the hippocampal CA1 region in vitro.

Group I metabotropic glutamate receptors interfere in different ways with pentylenetetrazole seizures, kindling, and kindling-related learning deficits.

LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, kindling, and kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of kindling induction, LY significantly depressed the progression of kindled seizure severity.