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Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors.

ABSTRACT: Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells. Primary endothelial cultures expressed NMDA receptor subunits and produced nitric oxide in response to co-agonists, glutamate and D-serine. In cerebral cortex in situ, immunoelectron microscopy revealed that endothelial cells express the GluN1 NMDA receptor subunit at basolateral membrane surfaces in an orientation suitable for receiving intercellular messengers from brain cells. In cortical slices, activation of astrocytes by two-photon flash photolysis of a caged Ca²⁺ compound or application of a metabotropic glutamate receptor agonist caused endothelial NO generation and local vasodilation. These effects were mitigated by NMDA receptor antagonists and conditional gene silencing of endothelial GluN1, indicating at least partial dependence on endothelial NMDA receptors. Our observations identify a novel astrocyte-endothelial vasodilatory signaling axis that could contribute to endothelium-dependent vasodilation in brain functional hyperemia.

SUBMITTER: Lu L

PROVIDER: S-EPMC6421257 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors.

Lu Lingling L Hogan-Cann Adam D AD Globa Andrea K AK Lu Ping P Nagy James I JI Bamji Shernaz X SX Anderson Christopher M CM

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20171026 3

Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by ...[more]

PMID: 29072857

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Project description:Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0?g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0?g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

Dataset Information

Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors.

Publications

Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors.

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