Andres Luis Buonanno, Ph.D.
Section on Molecular Neurobiology
Research at the Section on Molecular Neurobiology (SMN) has focused on investigating the activity-dependent functions of neurotrophic factors, known as Neuregulins (NRG), and their receptor ErbB4. Variants of these genes are risk factors for psychiatric and neurological disorders. Research at the SMN has shown that, by virtue of the selective expression of ErbB4 receptors in GABAergic inhibitory and dopaminergic neurons, the NRG-ErbB4 signaling pathway regulates numerous functions associated with excitation/inhibitory (E/I) balance, neurocircuit function and behaviors – in particular cognitive deficits known to be affected in schizophrenia, autism, obsessive-compulsive disorders and Alzheimer’s disease. Specifically, our group has shown that ErbB4 receptors: regulate dopaminergic neurotransmission by increasing dopamine D4 receptor (D4R) signaling, are co-expressed with D4Rs in neocortical fast-spiking parvalbumin-positive interneurons, and the functional interactions between D4 and ErbB4 receptors regulate synaptic plasticity and gamma oscillations, as well as behaviors cognitive behaviors associated with neurodevelopmental psychiatric disorders. More recently, we demonstrated that NRG variants are differentially trafficked either to neuronal soma or to axons, and that shedding of the biologically active NRG ectodomain by ADAM metalloproteinases is regulated by electrical activity. Our data suggest that somatic NRGs function in autocrine fashion to homeostatically regulate neuronal excitability, whereas NRGs trafficked to axons regulate myelination and synaptic properties. Our future goal is to identify how NRGs trafficked to distinct neuronal compartments may differentially regulate distinct cognitive parameters (i.e., attention, impulsivity, persevarative behaviors) that are affected in a number of psychiatric and neurological disorders.
My long-standing interest to understand how neural activity regulates the excitable and synaptic properties of excitable cells, particularly processes like synaptic potentiation/ depotentiation that underlie learning and memory, began during my graduate studies at Washington University when the field of molecular biology had not yet permeated into the neurosciences. For my dissertation, which was carried-out in the laboratory of Dr. John Merlie, I worked on cloning the first cDNAs and genes encoding nicotinic acetylcholine receptors (nAChRs). The goals of these experiments were to study how motoneuron-derived factors and motoneuron activity regulate the junctional and extra-junctional expression and functional properties of nAChRs in skeletal muscle. After receiving my Ph.D., those interests served as the basis for starting my research program at the NIH in 1988 that focused on two major lines of research: 1) how specific motorneuron activity patterns differentially regulate the slow and fast contractile properties of skeletal muscles, and 2) how activity, particularly via NMDA receptors that function as coincident-activity sensors (i.e., Hebbian properties), regulate synaptic plasticity and neuronal network properties during neurodevelopment to modulate associative learning and numerous cognitive functions.
Those general interests continue to guide my laboratory today as it focuses on the Neuregulin-ErbB pathway - a signaling network whose ligands are processed and released in response to activity and that regulate, through activation of its major neuronal receptor ErbB4, the plastic properties of synapses, the activity of neuronal networks and numerous behaviors. Understanding how this pathway regulates these neuronal functions became important, not only as a neurodevelopmental scientific question, but also because numerous genetic studies identified Neuregulin-1 (NRG1) and ErbB4 as “at risk genes” for schizophrenia and many of its endophenotypes. We also are finalizing work we began over twenty years ago that focused on understanding how distinct patterns of motor neuron activity differentially regulate the transcriptional programs that underlie the contractile properties of slow-twitch (red) and fast-twitch (white) muscles. Our group initially characterized DNA–regulatory sequences that were used to identify transcription factors differentially regulated by slow-patterned (10 Hz, tonic) and fast-patterned (100 Hz, phasic) activity, which are selectively targeted to muscle myonuclei in response to activity to regulate expression of contractile proteins that determine the slow- and fast-twitch properties of skeletal muscles. Our ultimate goal is to uncover how these transcription factors "sense" slow and fast patterns of depolarization because it has important implications for understanding how activity (experience) modulates the plastic properties of muscles and neurons.
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 October 16th, 2018