Skip to main content
NINDSNIMHNICHDNIDCDNEINIDCRNIANIAAANIDANHGRI NCCIHNIDDKNIEHSCCB

Profile Image

Senior Investigator

Andres L. Buonanno, Ph.D.

Porter Neuroscience Research Center
Building 35 Room 2C-1000
35 Convent Drive
Bethesda MD 20892-
Office: (301) 496-0170

Fax: (301) 496-9939
buonanno@helix.nih.gov

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. In 1988 he moved to NIH, where his group was involved in the initially cloning and characterization of glutamate receptors. 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. His group presently studies the role of the Neuregulin-ErbB receptor signaling pathway, recently associated with psychiatric disorders, in neural development, synaptic plasticity and behavior.




Neuregulin-ErbB Signaling Regulates Neuronal Activity: Relevance for Psychiatric Disorders

Neuregulins are a family of trophic and differentiation factors that signal via ErbB receptor tyrosine kinases. Polymorphisms in the Neuregulin1 (NRG1) and ErbB4 genes have been associated with an increased risk of schizophrenia and bipolar disorder. Importantly, a NRG1 polymorphism is associated with poor cognitive function, an endophenotype associated with these psychiatric disorders. We, and others, have shown that NRG/ErbB signaling regulates the expression of neurotransmitter receptors (for glutamate, GABA and acetylcholine), myelination, and neuronal migration. We found that activation of the NRG signaling pathway reverses long-term potentiation (LTP) at glutamatergic synapses. This is an intriguing finding given the importance of LTP for memory and cognition, and because of proposed deficits in glutamate neurotransmission associated with schizophrenia. Importantly, we recently demonstrated that NRG-1 elicits its effects on LTP by modulating the levels of dopamine, which in turn activates D4 receptors, a member of the group of dopamine D2-type receptors that are the main targets of many antipsychotics (e.g. clozapine).

Our laboratory is also studying the effects of NRGs on neural network activity, in collaboration with Dr. Andre Fisahn's lab at the Karolinska Institute. We found that NRG1 dramatically increases the power of hippocampal gamma oscillations without affecting the frequency. Our immunohistochemical analyses suggest that NRG1 actions on LTP reversal and network activity are mediated via ErbB4-positive inhibitory interneurons.

The novel functional link between NRG1, dopamine and glutamate, that appears to be mediated through ErbB4-expressing GABAergic interneurons, helps to understand the behavioral alterations observed in mice expressing reduced levels of NRG and ErbB4. Given the association of NRG1 and ErbB4 with schizophrenia, and the imbalances in glutamatergic and dopaminergic transmission associated with the disorder, our results could have important implications for understanding how the NRG signaling pathway may be altered in psychiatric disorders.For more information, please visit Dr. Buonanno's main lab site at http://smn.nichd.nih.gov/index.html




NRG-1 effects on kainate-induced gamma oscillations require ErbB4 and D4 receptor signaling.

NRG-1 effects on kainate-induced gamma oscillations require ErbB4 and D4 receptor signaling

Top: Triple immunofluorescence of hippocampal parvalbumin-positive GABAergic interneurons (blue) that are co-expressing ErbB4 (green) and dopamine D4 (red) receptors.

Bottom: NRG1 increases the power of kainate-induced gamma oscillations in rat hippocampal slices. The effects of NRG1 on gamma oscillations are blocked by a selective D4 receptor antagonist (L-745,870) and clozapine, an atypical antipsychotic that preferentially targets dopamine D4 receptors.

From: Andersson et al. 2012.

Staff Image
  • Katrina Furth, B.S.
    Graduate Student
    (301) 452-0946

  • Irina Karavanova, Ph.D.
    Biologist
    (301) 594-4641

  • Carolyn Keating, B.S.
    Post baccalaureate Fellow
    (301) 451-0940

  • Robert Mitchell, Ph.D.
    IRTA
    (301) 594-6860

  • Miguel Skirzewski, M.S.
    Visiting Fellow
    (301) 594-5214

  • Detlef Vullhorst, Ph.D.
    Senior Research Fellow

  • 1) Janssen MJ, Leiva-Salcedo E, Buonanno A (2012)
  • Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons
  • J Neurosc, 32, 13889-13895
  • 2) Shamir A, Kwon OB, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, Buonanno A (2012)
  • The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders
  • J Neurosc, 32, 2988-2997
  • 3) Andersson RH, Johnston A, Herman PA, Winzer-Serhan U, Karavanova I, Vullhorst D, Fisahn A, Buonanno A (2012)
  • Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors
  • Natl Acad Sci USA, 109, 13118-13123
  • 4) Neddens J, Fish KN, Tricoire L, Vullhorst D, Shamir A, Chung W, Lewis DA, McBain C and Buonanno A (2011)
  • 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
  • 5) Shamir A & Buonanno (2010)
  • Molecular and Cellular Characterization of Neuregulin-1 type IV Isoforms
  • J Neurochem, 2010 Mar 10
  • 6) Neddens J & Buonanno A (2009)
  • Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice
  • Hippocampus
  • 7) Neddens J, Vullhorst D, Paredes D, & Buonanno A (2009)
  • Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity
  • Commun Integr Biol , 2(3), 261-264
  • 8) Vullhorst D, et al. (2009)
  • Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus
  • J Neurosci , 29(39), 12255-12264
  • 9) Fisahn A, Neddens J, Yan L, & Buonanno A (2009)
  • Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia
  • Cereb Cortex, 19(3), 612-618
  • 10) Rana ZA, Gundersen K, & Buonanno A (2008)
  • Activity-dependent repression of muscle genes by NFAT
  • Proc Natl Acad Sci U S A, 105(15), 5921-5926
  • 11) Buonanno A, et al (2008)
  • Neuregulins and neuronal plasticity: possible relevance in schizophrenia
  • Novartis Found Symp , 289, 165-177
  • 12) Kwon OB, et al. (2008)
  • ) 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
  • 13) Karavanova I, Vasudevan K, Cheng J, & Buonanno A (2007)
  • Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice
  • Mol Cell Neurosci , 34(3), 468-480
  • 14) Kwon OB, Longart M, Vullhorst D, Hoffman DA, & Buonanno A (2005)
  • Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses
  • J Neurosci, 25(41), 9378-9383
  • 15) Rana ZA, Gundersen K, Buonanno A, & Vullhorst D (2005)
  • 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
  • 16) Longart M, Liu Y, Karavanova I, & Buonanno A (2004)
  • Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons
  • J. Comp. Neurol, 472(2), 156-172
View Pubmed Publication
View/Hide All Publications