Andres Luis Buonanno, Ph.D.
Section on Molecular Neurobiology
35 Covenant Dr Room 2C100
Bethesda, MD 20892-3713
The Section of Molecular Neurobiology (SMN) has been a major contributor of groundbreaking discoveries over the past 20 years regarding the role of the Neuregulin-ErbB4 signaling pathway in the developing and adult CNS. We, and others, demonstrated that NRG/ErbB4 signaling modulates glutamatergic synaptic plasticity, neuronal network activity (gamma oscillations) and dopamine balance. These effects arise from ErbB4 signaling in local GABAergic interneurons and dopaminergic projections that indirectly impinge on pyramidal neurons.
Schizophrenia, like autism and ADHD, is a developmental disorder with deficits in cognitive function as a core symptom. It is therefore significant that NRG1 and ErbB4 have been associated with risk for schizophrenia, and that subjects with "at risk" alleles exhibit numerous relevant endophenotypes - including low IQ and cognitive deficits.
Furthermore, we uncovered novel and paradigm-shifting functions of NRG/ErbB4 signaling. In particular, we found that NRG modulates dopamine levels and LTP, and it co-signals with dopamine D4 receptors in PV-FS interneurons to augment gamma oscillations. In addition, we identified a bidirectional autocrine regulatory loop between NRG2/ErbB4 and NMDARs selectively in GABAergic interneurons that challenges traditional concepts of NRG regulation and function. More recently, we also uncovered that the secondary structure of Neuregulins determine their subcellular targeting to either the axons or the somato-dendritic compartment of central neurons.
With the identification of direct targets of the Neuregulin/ErbB pathway in DAergic and GABAergic neurons, our goal is to elucidate the molecular mechanisms responsible for modulating synaptic and microcircuit properties that underlie working memory and other cognitive domains frequently associated with deficits in psychiatric disorders.
Dr. Buonanno's training as a molecular neuroscientist began at Washington University in St. Louis, where he developed a long-lived fascination for understanding how experience (i.e., activity) and genes interact during neurodevelopment to influence the plastic properties of synapses and neurocircuits. The main focus of his lab has been mostly in two areas of research: 1) understanding how the activity-dependent functions of the Neuregulin-ErbB4 signaling pathway regulates the plastic properties of synapses and cortical neurocircuits, and 2) investigating how distinct patterns of motorneuron activity regulate the fiber-type-specific properties of skeletal muscles during exercise. Understanding the functions of the NRG-ErbB4 signaling pathway is important because variants of these genes have been identified as major risk factors for schizophrenia and other neurodevelopmental disorders. In 2001 Dr. Buonanno was inducted as a member of the Latin American Academy of Sciences (ACAL).
Vullhorst D, Ahmad T, Karavanova I, Keating C, Buonanno A. Structural Similarities between Neuregulin 1-3 Isoforms Determine Their Subcellular Distribution and Signaling Mode in Central Neurons. J Neurosci. 2017;37(21):5232-5249.
Vullhorst D, Mitchell RM, Keating C, Roychowdhury S, Karavanova I, Tao-Cheng JH, Buonanno A. A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling. Nat Commun. 2015;6:7222.
Yan L, Shamir A, Skirzewski M, Leiva-Salcedo E, Kwon OB, Karavanova I, Paredes D, Malkesman O, Bailey KR, Vullhorst D, Crawley JN, Buonanno A. Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders. Mol Psychiatry. 2018;23(5):1233-1243.
Skirzewski M, Karavanova I, Shamir A, Erben L, Garcia-Olivares J, Shin JH, Vullhorst D, Alvarez VA, Amara SG, Buonanno A. ErbB4 signaling in dopaminergic axonal projections increases extracellular dopamine levels and regulates spatial/working memory behaviors. Mol Psychiatry. 2017.
Andersson RH, Johnston A, Herman PA, Winzer-Serhan UH, Karavanova I, Vullhorst D, Fisahn A, Buonanno A. Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors. Proc Natl Acad Sci U S A. 2012;109(32):13118-23.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Social and Behavioral Sciences
This page was last updated on June 21st, 2019