Dr. Mary E. Blue is a research scientist in the neuroscience laboratory at Kennedy Krieger Institute. She is also an associate professor in the Department of Neurology and Neuroscience at The Johns Hopkins University School of Medicine.
Dr. Blue graduated cum laude with her bachelor's degree in biology and art from Cornell College in Mount Vernon, Iowa in 1977. She received her doctoral degree from the Department of Cell Biology at the University of Texas Health Science Center at Dallas in Dallas, TX, in 1982. Dr. Blue continued her career as a post-doctoral fellow in the Department of Cell Biology and Neuroscience at Johns Hopkins University School of Medicine in Baltimore, MD, between 1982-1989 and has continued as research scientist at Kennedy krieger Institute from 1989 until the present. Dr. Blue acted as assistant professor in the Department of Neurology at Johns Hopkins University School of Medicine from 1992-1999. She continues as associate professor in the Department of Neurology since 2000 and serves as associate professor in the Johns Hopkins University School of Medicine in the Department of Neuroscience as well.
Our lab is interested in the role that neurotransmitters play in brain development and plasticity and in animal models of developmental and adult brain disorders. Our research has demonstrated that monoaminergic and glutamatergic neurotransmitter systems are both altered by and influence injury in models of hypoxia-ischemia and in developmental disorders such as autism and Rett syndrome (RTT). Our lab’s primary focus is on RTT, a debilitating developmental disorder that is caused by mutations in the X-linked gene that encodes for methyl CpG binding protein 2 (MeCP2). The phenotypic features of RTT include non-purposeful, stereotyped movements of hands, impaired mobility, intellectual disability, seizures, altered bone growth and premature osteoporosis and altered respiration. Unlike in autism, where brain size is increased, brain volume is reduced significantly in girls with RTT. Based on this, we hypothesized that RTT was a synaptic disorder, and given that glutamate is the most prevalent neurotransmitter in the brain, decided to characterize the expression of different types of glutamate receptors in post mortem samples of the prefrontal cortex from girls with RTT. We discovered that levels of glutamate receptors were higher in the cortex of girls with RTT, but only NMDA receptors were significantly overexpressed in young girls with RTT. This elevation occurs at the same time that glutamate levels are higher, indicating that homeostatic mechanisms regulating receptor expression have gone awry. These findings were the bases for clinical trials at KKI/Johns Hopkins investigating the efficacy of dextromethorphan, a NMDA receptor antagonist, for treatment of young girls with RTT.
Subsequent studies determined the effects of MeCP2 deficiency on brain development, bone growth and behavior in a mouse model for RTT developed by Adrian Bird. As in RTT, autoradiographic studies showed overexpression of NMDA receptors in the cortex of 2 weeks old Mecp2-null mice (2-4 years in human life). In other studies we found that MeCP2 deficiency impairs bone formation and affects bone strength and that treatment with zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity improves bone strength in MeCP2 deficient mice.
Our most recent studies in collaboration with the Kannan labs at Hopkins explore the role of glial-neuronal dysregulation in RTT. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms in RTT. We are investigating a new nanotherapeutic approach to target glia to attenuate brain inflammation/injury both in vitro and in vivo in Mecp2-null and Mecp2-heterozygous mice. Our ongoing studies are using dendrimer nanoparticles (4-6 nm) that intrinsically target ‘activated’ microglia to study the effects of the anti-inflammatory and antioxidant N-acetyl cysteine (NAC) and dendrimer-N-acetyl cysteine (D-NAC). Preliminary results indicate that D-NAC improves behavioral outcomes in MeCP2-deficient mice.
Nance E, Kambhampati SP, Smith ES, Zhang Z, Zhang F, Singh S, Johnston MV, Kannan RM, Blue ME (co-senior and corresponding author), Kannan S. Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome. J Neuroinflammation. 2017; 14: 252.
Grimm JC, Magruder JT, Wilson MA, Blue ME, Crawford TC, Troncoso JC, Zhang F, Kannan S, Sciortino CM, Johnston MV, Kannan RM, Baumgartner WA. Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury. Ann Thorac Surg. 2016; 102(3): 743-50.
Nance E*, Kambhampati SP*, Smith ES*, Zhang Z, Zhang F, Singh S, Johnston MV, Rangaramanujam K, Blue ME#, Kannan S. Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome. J Neuroinflammation. 2017; 14(1): 252.
Shapiro JR, Boskey AL, Doty SB, Lukashova L, Blue ME+. Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome. Bone. 2017; 99: 1-7.
Zhang F, Trent Magruder J, Lin YA, Crawford TC, Grimm JC, Sciortino CM, Wilson MA, Blue ME, Kannan S, Johnston MV, Baumgartner WA, Kannan RM. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. J Control Release. 2017; 249: 173-182.
Shapiro JR, Boskey AL, Doty SB, Lukashova L, Blue ME (2017). Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome. Bone. 99, 1-7.
Arnaoutakis GJ, George TJ, Wang KK, Wilson MA, Allen JG, Robinson CW, Haggerty KA, Weiss ES, Blue ME, Talbot CC Jr, Troncoso JC, Johnston MV, Baumgartner WA (2011). Serum levels of neuron-specific ubiquitin carboxyl-terminal esterase-L1 predict brain injury in a canine model of hypothermic circulatory arrest. J Thorac Cardiovasc Surg. 142(4), 902-910.e1.
Blue ME, Kaufmann WE, Bressler J, Eyring C, O'driscoll C, Naidu S, Johnston MV (2011). Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice. Anat Rec (Hoboken). 294(10), 1624-34.
Shapiro JR, Bibat G, Hiremath G, Blue ME, Hundalani S, Yablonski T, Kantipuly A, Rohde C, Johnston M, Naidu S (2010). Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations. Pediatr Res. 68(5), 446-51.
Jain D, Singh K, Chirumamilla S, Bibat GM, Blue ME, Naidu SR, Eberhart CG (2010). Ocular MECP2 protein expression in patients with and without Rett syndrome. Pediatr Neurol. 43(1), 35-40.
Allen JG, Weiss ES, Wilson MA, Arnaoutakis GJ, Blue ME, Talbot CC Jr, Jie C, Lange MS, Troncoso JC, Johnston MV, Baumgartner WA (2010). Hawley H. Seiler Resident Award. Transcriptional profile of brain injury in hypothermic circulatory arrest and cardiopulmonary bypass. Ann Thorac Surg. 89(6), 1965-71.
Tseng EE, Brock MV, Lange MS, Troncoso JC, Blue ME, Lowenstein CJ, Johnston MV, Baumgartner WA (2010). Glutamate excitotoxicity mediates neuronal apoptosis after hypothermic circulatory arrest. Ann Thorac Surg. 89(2), 440-5.
Weiss ES, Wang KK, Allen JG, Blue ME, Nwakanma LU, Liu MC, Lange MS, Berrong J, Wilson MA, Gott VL, Troncoso JC, Hayes RL, Johnston MV, Baumgartner WA (2009). Alpha II-spectrin breakdown products serve as novel markers of brain injury severity in a canine model of hypothermic circulatory arrest. Ann Thorac Surg. 88(2), 543-50.
Liu Y, Yoo MJ, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK (2008). Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease. J Neurosci. 28(51), 13805-14.
Boylan CB, Blue ME, Hohmann CF (2007). Modeling early cortical serotonergic deficits in autism. Behav Brain Res. 176(1), 94-108.
Williams JA, Barreiro CJ, Nwakanma LU, Lange MS, Kratz LE, Blue ME, Berrong J, Patel ND, Gott VL, Troncoso JC, Johnston MV, Baumgartner WA (2006). Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery. Ann Thorac Surg. 81(6), 2235-41; discussion 2241-2.
Barreiro CJ, Williams JA, Fitton TP, Lange MS, Blue ME, Kratz L, Barker PB, Degaonkar M, Gott VL, Troncoso JC, Johnston MV, Baumgartner WA (2006). Noninvasive assessment of brain injury in a canine model of hypothermic circulatory arrest using magnetic resonance spectroscopy. Ann Thorac Surg. 81(5), 1593-8.
Kaufmann WE, Johnston MV, Blue ME (2005). MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution.Brain Dev. 27 Suppl 1, S77-S87.
Patra RC, Blue ME, Johnston MV, Bressler J, Wilson MA (2004). Activity-dependent expression of Egr1 mRNA in somatosensory cortex of developing rats. J Neurosci Res. 78(2), 235-44.