GABA(A) Receptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca2+, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo

摘要

Neural activity regulates local increases in cerebral blood flow (Delta CBF) and the cortical metabolic rate of oxygen (Delta CMRO2) that constitutes the basis of BOLD functional neuroimaging signals. Glutamate signaling plays a key role in brain vascular and metabolic control; however, the modulatory effect of GABA is incompletely understood. Here we performed in vivo studies in mice to investigate how THIP (which tonically activates extrasynaptic GABA(A)Rs) and Zolpidem (a positive allosteric modulator of synaptic GABA(A)Rs) impact stimulation-induced Delta CBF, Delta CMRO2, local field potentials (LFPs), and fluorescent cytosolic Ca2+ transients in neurons and astrocytes. Low concentrations of THIP increased Delta CBF and Delta CMRO2 at low stimulation frequencies. These responses were coupled to increased synaptic activity as indicated by LFP responses, and to Ca2+ activities in neurons and astrocytes. Intermediate and high concentrations of THIP suppressed Delta CBF and Delta CMRO2 at high stimulation frequencies. Zolpidem had similar but less-pronounced effects, with similar dependence on drug concentration and stimulation frequency. Our present findings suggest that slight increases in both synaptic and extrasynaptic GABA(A)R activity might selectively gate and amplify transient low-frequency somatosensory inputs, filter out high-frequency inputs, and enhance vascular and metabolic responses that are likely to be reflected in BOLD functional neuroimaging signals.