GABAergic Regulation of Cerebral Microvascular Tone in the Rat

Abstract

Summary:The role of GABA in regulating cerebral mi crovessels was examined in the parenchyma of the hippocam pus and the surface of the neocortex. Microvessels were moni tored in in vitro slices using computer-assisted videomicros copy, and synaptically evoked field responses were simultaneously recorded. ,/-Aminobutyric acid (GAB A) and the GABAA receptor agonist, muscimol, elicited vasodilation in hippocampal microvessels, whereas the GABAB receptor agonist, badofen, elicited constriction. The muscimol-induced dilation persisted in the presence of the nitric oxide synthase inhibitor, N-nitro-L-arginine, indicating that this response is not mediated by nitric oxide. Inhibition of neuronal discharge ac tivity with tetrodotoxin did not alter this dilation, but it fully blocked the constrictor response to baclofen. These data sug gest that GABAB-mediated, but not GABAA-mediated, re sponses are dependent on action potential generation. The GABAA receptor antagonists, bicuculline and picrotoxin, elicConverging lines of evidence suggest that local neu rons are major participants in the regulation of regional cerebral blood flow (CBF). At rest, regional CBF is di rectly correlated with the level of local neuronal activity (Lou et aI., 1987). Furthermore, CBF increases in a spa tially and temporally precise manner during enhanced neuronal activity (Fox and Raichle, 1986). This vascular response frequently is dissociated from changes in re gional cerebral metabolism, suggesting that these blood flow changes are not necessarily a consequence of meta bolic alterations (Lenniger-Follert and Lubbers, 1976; Nakai et a!., 1983; Fox and Raichle, 1986; Lou et aI., 992ited constriction, suggesting a tonic dilatory influence by en dogenous GABA. Bicuculline-induced constriction was not at tenuated by tetrodotoxin. In contrast, these vessels were unre sponsive to the GABAB receptor antagonist, 2-hydroxysac lofen. Hippocampal microvessels dilated in response to mod erate hypoxia, and this response persisted in the presence of bicuculline, indicating that the hypoxia-induced dilation is not mediated by an action at GABAA receptors. In arterioles lo cated on the surface of the neocortex (i.e., not embedded in the parenchyma of the brain), muscimol elicited vasodilation, whereas bicuculline was ineffective. These results suggest that although these vessels are responsive to GABA, the local con centration of endogenous GABA is insufficient to elicit a tonic effect at rest. These findings raise the possibility that GABA plays a role in local neurovascular signaling in the parenchyma of the brain.

Pyramidal Neurons Are "Neurogenic Hubs" in the Neurovascular Coupling Response to Whisker Stimulation

“…7C). Such a conclusion is also supported by the limited vasomotor effect observed in cortical slices after bath application of GABA-A agonists (Fergus and Lee, 1997) or evoked firing of GABA interneurons (Cauli et al, 2004). Of interest, combined NMDA and GABA-A receptor antagonism cooperatively impairs both gamma oscillation (Cardin et al, 2009) and functional hyperemia (this study) in the barrel cortex, further emphasizing the role of neuronal synchronization in functional hyperemia, a response previously suggested to be initiated by the firing of inhibitory interneurons (Niessing et al, 2005).…”

“…4 B), a reduction remarkably similar to that reported after superfusion of the same compound for 1 or 2 h over the sensory cortex (Ϫ38%; Shi et al, 2008). Considering that astrocytes also express glutamate and GABA-A receptors (Conti et al, 1997;Cahoy et al, 2008), which activation by selective agonists induces vasodilatation independently of spiking activity (Fergus and Lee, 1997;Zonta et al, 2003;Lovick et al, 2005), we examined the relationship between EETs and excitatory and inhibitory neurotransmission. We coadministered MS-PPOH with MK-801 or picrotoxin and found no additive decline on the CBF response (Ϫ40.7 Ϯ 4.5%, p Ͻ 0.05, or 36.3 Ϯ 7.5%, p Ͻ 0.01) (Figs. 4 B, 5C, 6E), which suggests that EETs possibly act as signaling intermediaries for both pyramidal cells and GABA interneurons.…”

Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain

“…GABAergic signaling has been shown to influence the tone of cortical vessels ex vivo and mediates the cortical hyperemia induced by stimulation of the basal forebrain (23,24). In fact, GABAergic terminals arising from local interneurons innervate the cortical parenchymal microvasculature, including arterioles and capillaries (25).…”

Cortical GABA Interneurons in Neurovascular Coupling: Relays for Subcortical Vasoactive Pathways

“…Although they may possibly participate in the interneuron-driven vascular responses, no information is yet available on the release of vasoactive substances from astrocytes activated by VIP, NPY, or SOM. Moreover, release of such molecules from perivascular astrocytes, akin to the dilatory role of GABA on microvessels (Fergus and Lee, 1997), would offer no selectivity in vasomotor responses in contrast to neuropeptides acting on subtype-specific receptors to distinctly alter microvascular tone.…”