Biology subjects

Institoris, A.

Publications and source records attributed to Institoris, A..

3 recordsLinked to original sources

bioRxiv2022

Bidirectional and reciprocal control of astrocyte free calcium by modest fluctuations in external potassium

Astrocytes sense and respond to changes in the concentration of extracellular K+, and separately contribute to multiple physiological processes through Ca2+ dependent mechanisms. Yet, whether a modest change in [K+]o impacts astrocyte free Ca2+ remains unclear. Using relative or quantitative two-photon fluorescence Ca2+ imaging in acute brain slices or in vivo in the somatosensory cortex from Sprague Dawley rats and C57Bl/6 mice, we showed that changes to external K+ (+/-1mM to 2.5mM) reciprocally controls the astrocyte Rhod-2 or OGB-1 Ca2+-dependent fluorescence in the soma, major processes and endfeet. The astrocyte Ca2+ decrease when [K+]o was elevated was sensitive to lowering the external concentration of Ca2+, Cl-, and HCO3-, but not Na+. Unexpectedly, the phenomenon was blocked by inhibiting K-Cl cotransport. Picrotoxin induced ictal neural activity drove an analogous decrease of astrocyte Ca2+. K+ mediated cerebral arteriole dilation in brain slices was also sensitive to inhibiting K-Cl cotransport as well as whole-cell patching a peri-arteriole astrocyte which perturbs normal Ca2+, Cl- and HCO3- concentration gradients. These data reveal subtle, bidirectional regulation of astrocyte free Ca2 via fluctuations of [K+]o within the physiological range.

neuroscience↗

bioRxiv2020

Astrocytes amplify cerebral blood flow elevation to sustained cortical activation in the awake mouse

Brain requires increased local cerebral blood flow (CBF) for as long as necessary during neuronal activation to match O2 and glucose supply with demand - termed functional hyperemia. Ca2+ elevation in astrocytes can drive arteriole dilation to increase CBF, yet affirmative evidence for the necessity of astrocytes in functional hyperemia in vivo is lacking. In awake and active mice, we discovered that functional hyperemia is bimodal with a distinct early and late component whereby arteriole dilation progresses as sensory stimulation is sustained. Clamping astrocyte Ca2+ signaling in vivo by expressing a high-affinity plasma membrane Ca2+ ATPase (CalEx) reduces sustained but not brief sensory-evoked arteriole dilation. Reciprocally, elevating astrocyte free Ca2+ using chemogenetics selectively augments sustained but not brief hyperemia. Neither locomotion, arousal, nor changes in neuronal signaling account for the selective effect of astrocyte Ca2+ on the late phase of the CBF response. Antagonizing NMDA-receptors or epoxyeicosatrienoic acid production reduces only the late component of functional hyperemia, leaving brief increases in CBF to sensory stimulation intact. We propose that a fundamental role of astrocyte Ca2+ is to amplify functional hyperemia when neuronal activation is prolonged.

neuroscience↗

bioRxiv2020

Deregulation of brain endothelial CD2AP in Alzheimer's disease impairs Reelin-mediated neurovascular coupling

Genetic variations in CD2-associated protein (CD2AP) predispose to Alzheimers disease (AD) but the underlying mechanisms remain unknown. Here, we show that a cerebrovascular loss of CD2AP is associated with cognitive decline in AD and that genetic downregulation of CD2AP in brain endothelial cells impairs memory function in two distinct mouse models. Mice with reduced CD2AP in brain microvessels display decreased resting cerebral blood flow, impaired functional hyperemia and vasomotion. In brain endothelial cells, CD2AP regulates the levels and signaling of ApoE receptor 2 elicited by Reelin glycoprotein. Activation of the CD2AP-ApoER2 pathway with Reelin mitigates the toxic effects of A{beta} on resting blood flow and vasomotion of brain vessels depleted of CD2AP. Thus, we demonstrate that deregulation of CD2AP perturbs specific functions and segments of the cerebral microvasculature and propose that targeting CD2AP molecular partners may offer refined therapeutic strategies for the treatment of AD.

neuroscience↗