Abstract
Brain blood flow is unusual in being largely regulated by pericytes – contractile cells that enwrap capillaries. These cells express the cytoskeleton-associated protein Cyfip which has been linked to autism and intellectual disability, and cytoskeletal regulation is crucial for cells that need to contract and relax around capillaries. Using transgenic approaches and molecular techniques from the Kittler lab, and expertise in imaging in vivo and in brain slices and mathematical modelling from the Attwell lab, we will investigate the role of Cyfip in these cells which are crucial to regulating the energy supply that underlies neural computation.
References
1 Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C, Gong H, Richard-Loendt A, Huang W, Saito T, Saido TC, Brandner S, Sethi H, Attwell D. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365(6450):eaav9518, 2019.
2 Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nature Neurosci. 19, 1619-1627, 2016.
3 MacAskill, A.F., Rinholm, J.E., Twelvetrees, A.E., Arancibia-Carcamo, I.L., Muir, J., Fransson, A., Aspenstrom, P., Attwell, D. & Kittler, J. (2009) Miro1 is a calcium sensor for glutamate receptor dependent localization of mitochondria at synapses. Neuron 61, 541-555.
4 Davenport EC, Szulc B, Drew J, Taylor J, Morgan T, Higgs NF, Lopez-Domenech G and Kittler JT (2019) Autism and Schizophrenia-associated CYFIP1 regulates the balance of synaptic excitation and inhibition. Cell Reports 26:2037-2051.
5 López-Doménech G, Covill-Cooke C, Ivankovic D, Halff EF, Sheehan DF, Norkett R, Birsa N, and Kittler JT. Miro proteins coordinate microtubule and actin dependent mitochondrial transport and distribution. EMBO Journal. 2018 37: 321-336.