Regional blood flow within the brain is tightly coupled to regional neuronal activity, a process known as neurovascular coupling (NVC). In this study, we demonstrate the striking role of SUR2- and Kir6.1-dependent ATP-sensitive potassium (KATP) channels in control of NVC in the sensory cortex of conscious mice, in response to mechanical stimuli. We demonstrate that either globally increased (pinacidil-activated) or decreased (glibenclamide-inhibited) KATP activity markedly disrupts NVC; pinacidil-activation is capable of completely abolishing stimulus-evoked cortical hemodynamic responses, while glibenclamide slows and reduces the response. The response is similarly slowed and reduced in SUR2 KO animals, while animals expressing gain-of-function (GOF) mutations in Kir6.1, which underlie Cantú syndrome, exhibit baseline reduction of NVC as well as increased sensitivity to pinacidil. In revealing the dramatic effects of either increasing or decreasing SUR2/Kir6.1-dependent KATP activity on NVC, whether pharmacologically or genetically induced, the study has important implications both for monogenic KATP channel diseases and for more common brain pathologies.
GirouardHIadecolaC.Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985)2006;
100: 328–335.
2.
LongdenTAZhaoGHariharanA, et al.
Pericytes and the control of blood flow in brain and heart. Annu Rev Physiol2023;
85: 137–164.
3.
ZambachSACaiCHelmsHCC, et al.
Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion. Proc Natl Acad Sci U S A2021;
118: e2023749118.
4.
LongdenTANelsonMT.Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow. Microcirculation2015;
22: 183–196.
5.
LongdenTADabertrandFKoideM, et al.
Capillary K(+)-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci2017;
20: 717–726.
6.
NicholsCG.KATP channels as molecular sensors of cellular metabolism. Nature2006;
440: 470–476.
7.
InagakiNGonoiTClementJP, et al.
A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron1996;
16: 1011–1017.
8.
FlaggTPEnkvetchakulDKosterJC, et al.
Muscle KATP channels: recent insights to energy sensing and myoprotection. Physiol Rev2010;
90: 799–829.
9.
HuangYMcClenaghanCHarterTM, et al.
Cardiovascular consequences of KATP overactivity in Cantu syndrome. JCI Insight2018;
3.
10.
SanchoMKlugNRMughalA, et al.
Adenosine signaling activates ATP-sensitive K(+) channels in endothelial cells and pericytes in CNS capillaries. Sci Signal2022;
15: eabl5405.
11.
HariharanARobertsonCDGarciaDCG, et al.
Brain capillary pericytes are metabolic sentinels that control blood flow through a K(ATP) channel-dependent energy switch. Cell Rep2022;
41: 111872.
12.
AndoKTongLPengD, et al.
KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling. Dev Cell2022;
57: 1383–1399.e7. e1387.
13.
WellsJAChristieINHosfordPS, et al.
A critical role for purinergic signalling in the mechanisms underlying generation of BOLD fMRI responses. J Neurosci2015;
35: 5284–5292.
14.
SmelandMFMcClenaghanCRoesslerHI, et al.
ABCC9-related intellectual disability myopathy syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9. Nat Commun2019;
10: 4457.
15.
GrangeDKRoesslerHIMcClenaghanC, et al.
Cantu syndrome: Findings from 74 patients in the international Cantu syndrome registry. Am J Med Genet C Semin Med Genet2019;
181: 658–681.
16.
CooperPEReutterHWoelfleJ, et al.
Cantu syndrome resulting from activating mutation in the KCNJ8 gene. Hum Mutat2014;
35: 809–813.
17.
BrownsteinCATowneMCLuquetteLJ, et al.
Mutation of KCNJ8 in a patient with Cantu syndrome with unique vascular abnormalities – support for the role of K(ATP) channels in this condition. Eur J Med Genet2013;
56: 678–682.
18.
McClenaghanCMukadamMARoeglinJ, et al.
Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS. EMBO Mol Med2023;
15: e16883.
19.
Percie Du SertNHurstVAhluwaliaA, et al.
The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. J Cereb Blood Flow Metab2020;
40: 1769–1777.
20.
AlbertsonAJLandsnessECTangMJ, et al.
Normal aging in mice is associated with a global reduction in cortical spectral power and network-specific declines in functional connectivity. Neuroimage2022;
257: 119287.
21.
RosenthalZPRautRVYanP, et al.
Local perturbations of cortical excitability propagate differentially through large-scale functional networks. Cereb Cortex2020;
30: 3352–3369.
22.
WrightPWBrierLMBauerAQ, et al.
Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice. PLoS One2017;
12: e0185759.
23.
BauerAQKraftAWBaxterGA, et al.
Effective connectivity measured using optogenetically evoked hemodynamic signals exhibits topography distinct from resting state functional connectivity in the mouse. Cereb Cortex2018;
28: 370–386.
24.
MaYShaikMAKozbergMG, et al.
Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons. Proc Natl Acad Sci U S A2016;
113: E8463–E8471.
25.
WhiteBRBauerAQSnyderAZ, et al.
Imaging of functional connectivity in the mouse brain. PLoS One2011;
6: e16322.
26.
BergonziKMBauerAQWrightPW, et al.
Mapping functional connectivity using cerebral blood flow in the mouse brain. J Cereb Blood Flow Metab2015;
35: 367–370.
27.
Padawer-CurryJABowenRMJarangA, et al.
Wide-Field optical imaging in mouse models of ischemic stroke. Methods Mol Biol2023;
2616: 113–151.
28.
WhitesallSEHoffJBVollmerAP, et al.
Comparison of simultaneous measurement of mouse systolic arterial blood pressure by radiotelemetry and tail-cuff methods. Am J Physiol Heart Circ Physiol2004;
286: H2408–2415.
29.
SuzukiMLiRAMikiT, et al.
Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res2001;
88: 570–577.
30.
AdebiyiAMcNallyEMJaggarJH.Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice. Am J Physiol Heart Circ Physiol2011;
301: H1360–1368.
31.
UhlirovaHKilicKTianP, et al.
Cell type specificity of neurovascular coupling in cerebral cortex. Elife2016;
5.
32.
LeeLBoormanLGlendenningE, et al.
Key aspects of neurovascular control mediated by specific populations of inhibitory cortical interneurons. Cereb Cortex2020;
30: 2452–2464.
33.
IadecolaC.The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron2017;
96: 17–42.
34.
LeeJStileCLBiceAR, et al.
Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition. J Cereb Blood Flow Metab2021;
41: 841–856.
35.
HosfordPSChristieINNiranjanA, et al.
A critical role for the ATP-sensitive potassium channel subunit K(IR)6.1 in the control of cerebral blood flow. J Cereb Blood Flow Metab2019;
39: 2089–2095.
36.
LahmannCKramerHBAshcroftFM.Systemic administration of glibenclamide fails to achieve therapeutic levels in the brain and cerebrospinal fluid of rodents. PLoS One2015;
10: e0134476.
37.
BanksWAGreigNH.Small molecules as Central nervous system therapeutics: old challenges, new directions, and a philosophic divide. Future Med Chem2019;
11: 489–493.
38.
NemotoEM.Cerebral oximetry by near infrared spectroscopy measures cerebral haemoglobin oxygen saturation and the balance between supply and demand, not cerebral blood flow. Br J Neurosurg1999;
13: 93–95.
39.
NelsonPTJichaGAWangWX, et al.
ABCC9/SUR2 in the brain: implications for hippocampal sclerosis of aging and a potential therapeutic target. Ageing Res Rev2015;
24: 111–125.
40.
GrangeDKNicholsCGSinghGK, et al. Cantu syndrome and related disorders. In: PagonRAAdamMPArdingerHH (eds) GeneReviews(R).
Seattle, WA:
University of Washington, 2014.
41.
NelsonPTWangWXPartchAB, et al.
Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. J Neuropathol Exp Neurol2015;
74: 75–84.
42.
NelsonPTWangWXWilfredBR, et al.
Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging. J Neurochem2015;
134: 1026–1039.
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