Biology subjects

Bekar, L. K.

Publications and source records attributed to Bekar, L. K..

3 recordsLinked to original sources

bioRxiv2020

Calcium-independent astrocytic lipid release modulates neuronal activity through Kv channels

An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.

neuroscience↗

bioRxiv2019

Serotonin, norepinephrine and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

Changes in extracellular potassium ([K+]e) modulate neuronal networks via changes in membrane potential, voltage-gated channel activity and alteration of transmission at the synapse. Given the limited extracellular space in the CNS, potassium clearance is crucial. As activity-induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte-specific Na+/K+-ATPase (NKA), any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity ("signal-to-noise") in somatosensory cortex, we hypothesize that [K+]e may be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K+]e in connection to effects on cortical evoked response amplitude and adaptation in male mice. Using extracellular field and K+ ion-selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K+]e regulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K+ recovery, adaptation and field post-synaptic potential amplitude were disrupted by barium (200 {micro}M), whereas NE and ACh effects were disrupted by ouabain (1 {micro}M) or iodoacetate (100 {micro}M). Considering the impact [K+]e can have on many network functions; it seems highly efficient that neuromodulators regulate [K+]e to exert their many effects. This study provides functional significance for astrocyte-mediated buffering of [K+]e in neuromodulator-mediated shaping of cortical network activity. Significance statementWe demonstrate that the neuromodulators serotonin, norepinephrine, and acetylcholine all have distinct effects on astrocyte-mediated extracellular potassium regulation and that these differential actions are associated with the different effects of the neuromodulators on cortical networks. By affecting astrocytic potassium regulation, long-range neuromodulatory networks can rapidly and efficiently affect broad areas of the brain. Given that neuromodulatory networks are at the core of our behavioral state and determine how we interact with our environment, these studies highlight the importance of basic astrocyte function in general cognition and psychiatric disorders.

neuroscience↗

bioRxiv2019

Acute inflammatory events attenuate high-sucrose diet-induced neurodegenerative processes in reproductively normal female wild-type mice

It is known that diabetic and chronic inflammatory conditions can increase the risk of Alzheimers disease (AD)-like neurodegeneration in isolation. As certain elements of the diabetic/pre-diabetic state may sensitize the brain to inflammatory insult (i.e. excess glucocorticoid activity), there is reason to believe that obesogenic and inflammatory factors may accelerate neurodegeneration in a synergistic manner. Also, given that most AD research utilizes male animal models despite increased prevalence of AD among women, we sought to characterize elements of the established (in males) high-sucrose model of neurodegeneration, for the first time, in reproductively normal (pre-menopausal) female mice. A high-sucrose diet (20% of the drinking water) was combined with systemic intraperitoneal lipopolysaccharide (LPS) injections (0.1 mg/kg; 1x/month over 3 months) over seven months in reproductively normal female wild-type mice (C57Bl/6; n=10/group). Although a deleterious effect was hypothesized, low-dose LPS proved to protect against high sucrose diet-induced pathologies in female wild-type mice. Results from our high-sucrose group confirmed that a high-sucrose diet is a mild model of neurodegeneration in wild-type females, as evidenced by exaggerated glucocorticoid expression, spatial learning deficits, irregularities within the insulin pathway, and increased {beta}-amyloid production and Tau phosphorylation. While LPS had little to no effect in isolation, it exerted a protective influence when added to animals sustained on a high-sucrose diet. Corticosterone homeostasis, and levels of amyloid-{beta} (A{beta}) and pTau were rescued following addition of LPS. The work presented supports a high-sucrose diet as a model of mild neurodegeneration in female mice and highlights a protective role for transient inflammation against dietary-insult that may be sex dependent.

neuroscience↗