Elizabeth C. Ballinger
B.S. University of California-Davis, 2008
8th Year MSTP
4th Year Medical Student
Advisor: Lorna Role, PhD
Department: Neurobiology and Behavior, Stony Brook University
Graduate Program: Neuroscience
Title: Phenotypic Effects of MeCP2 Deletion from Cholinergic Neurons
Abstract:
Rett Syndrome (RTT) is an autism spectrum disorder that affects approximately 1 in 20,000 girls and is caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2). The cholinergic system appears to be particularly important in RTT, as decreases in cholinergic markers have been correlated with increased clinical severity in patients with RTT. Schaaf and Zoghbi have developed a powerful transgenic mouse model, whereby MeCP2 is selectively deleted in cholinergic neurons only, to facilitate study of the contribution of this cholinergic lesion to the overall phenotype of RTT. Interestingly, this model exhibits a selective deficit in recognition memory, a form of declarative memory that has been shown by lesion and electrophysiological studies to be dependent upon cholinergic signaling in the perirhinal cortex (PRH). This memory deficit may map onto the intellectual disability seen in patients with RTT, however, its molecular and electrophysiological underpinnings are unknown. We use optogenetics and in vivo electrophysiology to selectively activate cholinergic neurons in the Nucleus Basalis of Meynert (NBM), the cholinergic source nucleus that innervates the PRH, while simultaneously recording the effects of this selective activation in the PRH. We have demonstrated not only that NBM opto-stimulation modulates both the rate and variability of firing among PRH neurons, but that this modulation is impaired among selective cholinergic MeCP2 knock-out mice. Additionally, we have found a decrease in expression of ChAT, the cholinergic synthetic enzyme, among selective MeCP2 knock-out mice specifically in the NBM, while expression in other cholinergic nuclei is spared. This suggests that the recognition memory deficit seen among cholinergic MeCP2 knock-out mice is mediated by deficient acetyl choline synthesis and signaling in the NBM-PRH circuit and that other cholinergic nuclei are robust to MeCP2 deletion. These results may help guide the development of future targeted treatment strategies for patients with RTT.
Publications:
(MSTP-supported publications indicated with an *)
Jiang, L., Kundu, S., Lederman, J. D., López-Hernández, G. Y., Ballinger, E. C., Wang, S., & Role, L. W. (2016). Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits. Neuron, 90(5), 1057-1070.
Ballinger, E.C., Ananth, M., Talmage, D.A., Role, L.W. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Impairments. Neuron. (review, submitted).
Ballinger, E., Cordeiro, L., Chavez, A., Hagerman, R. and Hessl, D. (2014) Emotion Potentiated Startle in Fragile X Syndrome. Journal of Autism and Developmental Disorders.
Schneider, A., Ballinger, E., Cordeiro, L., Chavez, A., Olichney, J., Niese, A., Hagerman, R., Hessl, D. (2012) Prepulse Inhibition in patients with Fragile X related Tremor and Ataxia. Neurobiology of Aging, 33(6), 1045-53.
Cordeiro, L., Ballinger, E., Hagerman ,R., and Hessl, D. (2011) Clinical Assessment of DSM-IV anxiety disorders in fragile X syndrome: Prevalence, characterization and the role of intellectual disability in diagnosis. Journal of Neurodevelopmental Disorders, 3(1), 57-67.
Yuhas, J., Cordeiro, L., Tassone, F., Ballinger, E., Schneider, A., Campbell, A., Ornitz, E., Long, J., Hagerman, R. and Hessl, D. (2011) Brief Report: Sensorimotor Gating in Idiopathic Autism and Autism Associated with Fragile X Syndrome. Journal of Autism and Developmental Disorders, 41(2), 248-53.
