Department of Neurosciences
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.
Overactivation of glutamate receptors is responsible for oligodendrocyte death and axonal disruption. Axons are injured directly by ionic mechanisms resulting in toxic accumulation of intracellular Na+ and Ca2+ while astrocytes due to reversal of Na+-dependent glutamate transporters release excessive glutamate leading to injury of oligodendrocytes and the myelin they produce.
Another novel finding of our studies discovered that the mechanisms of ischemic WM injury change as a function of age. Ischemic WM injury in older mice is predominately mediated by excitotoxicity due to earlier and more robust glutamate release due to an upregulation of glutamate transporter GLT-1. Moreover, interruption of the essential first stage of ionic dysfunction, such as removal of extracellular Ca2+ or blockade of Na-Ca exchanger, does not prevent injury in older axons while blockade of NMDARs worsens axon function recovery in the older WM.
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.
1. 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 Res42(1):19-34. PMID: 26915104; PMCID: PMC5357169
2. 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
3. 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
4. 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
5. 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
6. 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
7. Baltan S. (2015) 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
8. 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
9. Baltan S. (2014) Excitotoxicity and mitochondrial dysfunction underlie age-dependent ischemic white matter injury. Adv Neurobiol 11:151-70. PMID: 25236728
10. 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
11. 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
12. Baltan S. (2012) Histone deacetylase inhibitors preserve function in aging axons. J Neurochem 123 Suppl 2:108-15. PMID: 23050648; PMCID: PMC3481173
13. 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
14. 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
15. 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
16. 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