GABA_AReceptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca²⁺, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo

Abstract

Neural activity regulates local increases in cerebral blood flow (ΔCBF) and the cortical metabolic rate of oxygen (ΔCMRO2) 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 GABAARs) and Zolpidem (a positive allosteric modulator of synaptic GABAARs) impact stimulation-induced ΔCBF, ΔCMRO2, local field potentials (LFPs), and fluorescent cytosolic Ca(2+) transients in neurons and astrocytes. Low concentrations of THIP increased ΔCBF and ΔCMRO2 at low stimulation frequencies. These responses were coupled to increased synaptic activity as indicated by LFP responses, and to Ca(2+) activities in neurons and astrocytes. Intermediate and high concentrations of THIP suppressed ΔCBF and ΔCMRO2 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 GABAAR 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.

Activity‐dependent calcium, oxygen, and vascular responses in a mouse model of familial hemiplegic migraine type 1

“…34 We compared and correlated changes elicited in synaptic activity (LFP amplitudes) to corresponding increases in astroglial and neuronal Ca 21 activities, CBF, and CMRO 2 . Because LFP amplitudes correlate strongly with the amplitudes of excitatory postsynaptic currents, 12 our findings suggest that, for a given 40 and cerebellar parallel fiber terminals. 23,30,32,35,36 In contrast, activity-dependent increases in CBF are assumed to be controlled mainly by Ca 21 -dependent mechanisms in neuronal and astroglial networks.…”

“…In comparison, in FHM1 mice, somatosensory stimulation elicited smaller increases in intracellular Ca 21 activities in both neurons and astrocytes and smaller CBF responses than in WT mice. 12,26 The reduced Ca 21 responses in both cell types would contribute to the reduced neurovascular coupling response observed in FHM1 mice. It should be noted that part of the somatosensory response in astrocytes emerges from noradreanaline release from locus coeruleus projections and is suppressed in anesthetized mice.…”

“…The end-expiratory CO 2 level and blood pressure were continuously monitored and adjusted, when necessary, to maintain physiological conditions. For details, see Jessen et al 12 35-7.45).…”

Fast Ca2+ responses in astrocyte end‐feet and neurovascular coupling in mice

“…The LFP ( n = 13) and CBF ( n = 8) traces were averaged over 15 s, 1 Hz stimulations. At 1 µM, THIP reduced interneuron activity (Jessen et al, ), as reflected in larger fEPSPs ( n = 13, 1 Hz: p < 0.005; 3 Hz: p < 0.005, t‐test) and CBF responses ( n = 8, 1 Hz: p < 0.05, t ‐test). At 100 µM, THIP reduced the activation of all neurons, leading to a reduction in the size of the fEPSPs ( n = 13, 1 Hz: p < 0.05; 3 Hz: p < 0.05, t ‐test) and CBF responses ( n = 8, 3 Hz: p < 0.005, t ‐test).…”

“…Next, the inhibitory system of the whisker barrel cortex was targeted with THIP, which tonically activates extrasynaptic GABA A R. The effect of THIP on CBF and EPSP was presented and discussed in our earlier work (Jessen et al, ). From that previous study, we knew that a 1 µM dose of THIP primarily affects inhibitory interneurons, leading to general disinhibition that is reflected in larger fEPSPs and CBF responses to 1 Hz whisker pad stimulation (raw data example in Figure e).…”