Senior Investigator
Andres
Buonanno,
Ph.D.
Section on Molecular Neurobiology
Dr. Buonanno received his Ph.D. in Molecular Biology from Washington University in St. Louis where he worked with John Merlie on the initial cloning of acetylcholine receptor genes, and studying their transcriptional regulation by electrical activity and during development. During his tenure at Washington University, 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. In 1988 he moved to NIH, where his group was involved in the initial cloning and characterization of glutamate receptors. Originally, his lab focused on the identification of transcription factors that regulate developmental and activity-dependent expression of NMDA receptors and muscle genes. In 1999 Dr. Buonanno became a Senior Investigator. More recently, the main focus of his lab has turned to understanding how the activity-dependent functions of the Neuregulin-ErbB4 signaling pathway regulates the plastic properties of synapses and cortical neurocircuits that underlie behaviors and cognitive processes with relevance to psychiatric disorders. 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).
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Neuregulin-ErbB Signaling Regulates Neuronal Activity: Relevance for Psychiatric Disorders
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. For more information, please see Dr. Buonanno's lab webpage at https://irp.nih.gov/pi/andres-buonanno.
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Differential trafficking of Neuregulin isoforms in hippocampal neurons
A) Unprocessed single transmembrane proNRG1-type I accumulates as puncta atop subsurface cisterns on the soma and proximal dendrites of hippocampal neurons, whereas axons identified with Ankyrin G (green) are devoid of puncta. B) Glutamate stimulation promotes proNRG1 cleavage and ectodomain shedding, and this processing is blocked by NMDA receptor (AP5) or metalloprotease (GM6001) inhibitors. C) In contrast to proNRG1-type I, dual transmembrane NRG3 accumulates as a processed protein in axons (GFP-labeled) and away from cell bodies (not shown). D) Schematic illustration emphasizing the differential subcellular distribution of single-pass (NRG1-types I/II, NRG2) and dual-pass (NRG1-type III, NRG3) transmembrane NRGs in neurons, which can mediate distinct functions.
From: Vullhorst, Ahmad et al. JNS 2017
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Tanveer Ahmad, RN, BSN, CCRP
Postdoctoral Visiting Fellow
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Marie Cronin, B.A.
Post baccalaureate Fellow
301-594-0570
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Larissa Erben, M.Sc
Graduate Student
301-594-6860
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Irina Karavanova, Ph.D.
Biologist
(301) 496-3298
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Ricardo Murphy, B.S.
Volunteer
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Sonu Singh, Ph.D.
Postdoctoral Visiting Fellow
301-402-8415
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Miguel Skirzewski, Ph.D.
Visiting Postdoctoral Fellow
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Eric Starr, Ph.D.
Postdoctoral Visiting Fellow
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Detlef Vullhorst, Ph.D.
Senior Research Fellow
301-451-0942
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1) Erben L, Buonanno A (2019)
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Detection and Quantification of Multiple RNA Sequences Using Emerging Ultrasensitive Fluorescent In Situ Hybridization Techniques
- Curr Protoc Neurosci
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2) Erben L, Ming-Xiao H, Laeremans A, Park E, Buonanno A (2018)
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A Novel Ultrasensitive In Situ Hybridization Approach to Detect Short Sequences and Splice Variants with Cellular Resolution
- Mol Neurobiol, 55, 6169-6181
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3) Skirzewski M, Karavanova I, Shamir A, Erben L, Garcia-Olivares J, Hoon Shin J, Vullhorst D, Alvarez V, Amara S, Buonanno A (2018)
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ErbB4 Signalling in Dopaminergic Axonal Projections Increases Extracellular Dopamine Levels and Regulates Spatial/Working Memory Behaviors
- Mol Psychiatry, 23, 2227-2237
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4) 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 (2018)
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Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders
- Mol Psychiatry, 23, 1233-1243
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5) Vullhorst D, Ahmad T, Karavanova I, Keating C, Buonanno A (2017)
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Structural similarities between neuregulin 1-3 isoforms determine their subcellular distribution and signaling mode in central neurons
- J Neurosc, 37, 5232-5249
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6) Vullhorst D, Mitchell RM, Keating C, Roychowdhury S, Karavanova I, Tao-Cheng JH, Buonanno A (2015)
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A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling
- Nat Commun , 6, 7222
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7) Mitchell RM, Janssen MJ, Karavanova I, Vullhorst D, Furth K, Makuskey A, Markey S, Buonanno A (2013)
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ErbB4 receptor reduces synaptic GABAA currents independently of its tyrosine kinase activity
- Proc Natl Acad Sci USA, 110, 19603-19608
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8) Andersson RH, Johnston A, Herman PA, Winzer-Serhan U, Karavanova I, Vullhorst D, Fisahn A, Buonanno A (2012)
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Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors
- Natl Acad Sci USA, 109, 13118-13123
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9) Shamir A, Kwon OB, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, Buonanno A (2012)
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The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders
- J Neurosc, 32, 2988-2997
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10) Janssen MJ, Leiva-Salcedo E, Buonanno A (2012)
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Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons
- J Neurosc, 32, 13889-13895
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11) Neddens J, Fish KN, Tricoire L, Vullhorst D, Shamir A, Chung W, Lewis DA, McBain C and Buonanno A (2011)
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Expression of ErbB4 is consistently restricted to interneurons in the frontal cortex of humans, rhesus monkeys, and rodents: Implications for neuregulin signaling and schizophrenia
- Biol Psychiatry , 70, 636-645
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12) Shamir A & Buonanno (2010)
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Molecular and Cellular Characterization of Neuregulin-1 type IV Isoforms
- J Neurochem, 2010 Mar 10
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13) Neddens J & Buonanno A (2009)
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Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice
- Hippocampus
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14) Neddens J, Vullhorst D, Paredes D, & Buonanno A (2009)
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Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity
- Commun Integr Biol , 2(3), 261-264
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15) Vullhorst D, et al. (2009)
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Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus
- J Neurosci , 29(39), 12255-12264
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16) Fisahn A, Neddens J, Yan L, & Buonanno A (2009)
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Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia
- Cereb Cortex, 19(3), 612-618
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17) Rana ZA, Gundersen K, & Buonanno A (2008)
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Activity-dependent repression of muscle genes by NFAT
- Proc Natl Acad Sci U S A, 105(15), 5921-5926
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18) Buonanno A, et al (2008)
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Neuregulins and neuronal plasticity: possible relevance in schizophrenia
- Novartis Found Symp , 289, 165-177
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19) Kwon OB, et al. (2008)
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) Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors
- Proc Natl Acad Sci U S A , 105(40), 15587-15592
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20) Karavanova I, Vasudevan K, Cheng J, & Buonanno A (2007)
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Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice
- Mol Cell Neurosci , 34(3), 468-480
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21) Kwon OB, Longart M, Vullhorst D, Hoffman DA, & Buonanno A (2005)
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Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses
- J Neurosci, 25(41), 9378-9383
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22) Rana ZA, Gundersen K, Buonanno A, & Vullhorst D (2005)
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Imaging transcription in vivo: distinct regulatory effects of fast and slow activity patterns on promoter elements from vertebrate troponin I isoform genes
- J. Physiol, 562(Pt 3), 815-828
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23) Longart M, Liu Y, Karavanova I, & Buonanno A (2004)
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Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons
- J. Comp. Neurol, 472(2), 156-172
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