Selva Baltan, M.D., Ph.D.
Associate Professor, Molecular Medicine, CCLCM-CWRU
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 444-3972
Fax: (216) 444-7927
Failure to consider white matter (WM) injury is a critical gap in the development of a successful stroke therapy. As mechanisms of WM injury differ from those in gray matter and change with age, an ideal stroke therapeutic must not only be directed towards neuronal and axonal protection across age, but also must restore function when applied after injury. My research focuses on mechanisms of brain cell damage following stroke in WM in a region-specific and age-specific manner. Experimental approaches in my lab include optic nerve and corpus callosum slice models, employing electrophysiological recordings, and advanced microscopy techniques such as confocal, two-photon microscopy and 3D electron microscopy. Our current focus is on elucidating the mechanisms of post-ischemic protection conferred by Class I HDAC inhibition in young and aging WM and the gene regulatory mechanisms underlying this protective phenomenon. Our hypothesis is that Class I HDAC activation mediates WM ischemic injury by contributing to increased oxidative stress and impairing mitochondrial structure and function. Moreover, we are investigation whether oligodendrocytes and astrocyte support axon function by providing lactate as an alternative energy substrate during ischemia.
Currently we are working on the role of protein acetylation and mitochondrial dynamics in WM stroke and expanded our interest to neurodegenerative diseases such as Multiple Sclerosis and Alzheimer ’s disease that involve WM.
Chinthasagar Bastian, MBBS, PhD
1. Baltan S, Bastian C, Quinn J, Aquila D, McCray A, Brunet S. (2018) CK2 inhibition protects white matter from ischemic injury. Neurosci Lett. 687:37-42. PMID: 30125643
2. Bastian C, Quinn J, Tripathi A, Aquila D, Dutta AMR, Baltan S, Brunet S. (2018) CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways. Neurobiol Dis. Jun 23. pii: S0969-9961(18)30149-9. PMID: 29944965
3. Bastian C, Zaleski J, Stahon K, Parr B, McCray A, Day J, Brunet S, Baltan S. (2018) NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels. J Neurosci.38(28):6247-6266. PMID: 29891729; PMCID: PMC6041791
4. Parpura V, Fisher ES, Lechleiter JD, Schousboe A, Waagepetersen HS, Brunet S, Baltan S, Verkhratsky A. (2017) Glutamate and ATP at the Interface Between Signaling and Metabolism in Astroglia: Examples from Pathology. Neurochem Res. 42(1):19-34. PMID: 26915104; PMCID: PMC5357169
5. Hu X, Hou H, Bastian C, He W, Qiu S, Ge Y, Yin X, Kidd GJ, Brunet S, Trapp BD, Baltan S, Yan R. (2017) BACE1 regulates the proliferation and cellular functions of Schwann cells. Glia 65(5):712-726. PMID: 28191691; PMCID: PMC5357169
6. Provencio JJ, Swank V, Lu H, Brunet S, Baltan S, Khapre RV, Seerapu H, Kokiko-Cochran ON, Lamb BT, Ransohoff RM. (2016) Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors. Brain Behav Immun. 54:233-42. PMID: 26872422; PMCID: PMC4828315
7. Yin X, Kidd GJ, Ohno N, Perkins GA, Ellisman MH, Bastian C, Brunet S, Baltan S, Trapp BD (2016) Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling. J Cell Biol. 215(4):531-542. PMID: 27872255; PMCID: PMC5119941
8. Stahon KE, Bastian C, Griffith S, Kidd GJ, Brunet S, Baltan S. (2016) Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter. J Neurosci. 36(39):9990-10001. PMID: 27683897; PMCID: PMC5039264
9. Saab AS, Tzvetavona ID, Trevisiol A, Baltan S, Dibaj P, Kusch K, Möbius W, Goetze B, Jahn HM, Huang W, Steffens H, Schomburg ED, Pérez-Samartín A, Pérez-Cerdá F, Bakhtiari D, Matute C, Löwel S, Griesinger C, Hirrlinger J, Kirchhoff F, Nave KA. (2016) Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism. Neuron 91(1):119-32. PMID: 27292539
10. Baltan S. (2016) Age-specific localization of NMDA receptors on oligodendrocytes dictates axon function recovery after ischemia. Neuropharmacology pii: S0028-3908(15)30107-6. PMID: 26407763; PMCID: PMC4808487
11. Baltan S. (2015) Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? Metab Brain Dis. 30(1):25-30. PMID: 25034458; PMCID: PMC4297510
12. Baltan S. (2014) Excitotoxicity and mitochondrial dysfunction underlie age-dependent ischemic white matter injury. Adv Neurobiol. 11:151-70. PMID: 25236728
13. Murphy SP, Lee RJ, McClean ME, Pemberton HE, Uo T, Morrison RS, Bastian C, Baltan S. (2014) MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. J Neurochem. 129(3):509-15. PMID: 24147654
14. Baltan S, Morrison RS, Murphy SP. (2013) Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury. Neurotherapeutics 10(4):798-807. PMID: 23881453; PMCID: PMC3805855
15. Baltan S. (2012) Histone deacetylase inhibitors preserve function in aging axons. J Neurochem. 123 Suppl 2:108-15. PMID: 23050648; PMCID: PMC3481173
16. Baltan S, Bachleda A, Morrison RS, Murphy SP. (2011) Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Transl Stroke Res. 2(3):411-23. PMID: 21966324; PMCID: PMC3182145
17. Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS. (2011) Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci. 31(11):3990-9. PMID: 21411642; PMCID: PMC3061553
18. Baltan S, Inman DM, Danilov CA, Morrison RS, Calkins DJ, Horner PJ. (2010) Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration. J Neurosci. 30(16):5644-52. PMID: 20410117; PMCID: PMC2884009
19. Baltan S, Besancon EF, Mbow B, Ye Z, Hamner MA, Ransom BR. (2008) White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci. 28(6):1479-89. PMID: 18256269
Findings from a recent study conducted by researchers in the Department of Neurosciences suggest that a grape-rich diet can improve functional recovery following stroke by strengthening the network of cells that protect axons found in white matter, as well as conserving axonal energy production. A grape powder diet has previously been shown to protect gray matter against ischemic injury, but until now, its effect on white matter—the part of the brain most damaged by stroke—has been largely unknown.
Selva Baltan and Sylvain Brunet received a 2 year, $275,000 R21 grant from NINDS entitled "Casein Kinase 2 signaling in axonal injury". Their approach combines electrophysiology, biochemistry, RNA interference in oligodendrocyte cell lines, confocal and 2-photon imaging, tests of mitochondrial function, and 3-dimensional electron microscopy in order to define which glial cell type is injured by CK2 signaling and to establish that CK2 signaling impairs mitochondrial dynamics, function, and ultrastructure. These studies are designed to provide fundamentally important new insights into the physiological and pathophysiological regulation of CK2 signaling in white matter.