title: GABAA Receptor-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.
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Sanne Barsballe
authors.initials: SB
authors.lastname: Jessen
authors.affiliation: Biological Faculty Moscow State University, 119234 Moscow, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Brazhe
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Barbara Lykke
authors.initials: BL
authors.lastname: Lind
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Mathiesen
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Thomsen
authors.affiliation: Synaptic Physiology Laboratory, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark Department of Clinical Neurophysiology, Glostrup Hospital, 2600 Glostrup, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauritzen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004558:Electric Stimulation; D007839:Functional Laterality; D018755:GABA Agonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010313:Partial Pressure; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000166:cytology* / Q000502:physiology*; D013449:Sulfonamides / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014738:Vibrissae / Q000294:innervation; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D011725:Pyridines; D011963:Receptors, GABA-A; C558809:SR1001; D013449:Sulfonamides; D013844:Thiazoles; D004533:Egtazic Acid; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; C015542:gaboxadol; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
keywords: CMRO2; THIP; Zolpidem; blood flow; extrasynaptic/synaptic GABAAR; in vivo ca2+-imaging