title: Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
abstract: BACKGROUND
  Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice.
  
  
  METHODS
  We determined the expression of neuregulin 1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10-16 weeks) and studied the effects of ErbB inhibition on long-term potentiation in hippocampal area cornu ammonis 1 and on hippocampus-dependent contextual fear memory.
  
  
  RESULTS
  We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in long-term potentiation, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice.
  
  
  CONCLUSIONS
  Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS.
authors.affiliation: Center for Neural Science, New York University, New York, New York, USA.
authors.forename: Hanoch
authors.initials: H
authors.lastname: Kaphzan
authors.forename: Pepe
authors.initials: P
authors.lastname: Hernandez
authors.forename: Joo In
authors.initials: JI
authors.lastname: Jung
authors.forename: Kiriana K
authors.initials: KK
authors.lastname: Cowansage
authors.forename: Katrin
authors.initials: K
authors.lastname: Deinhardt
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D017204:Angelman Syndrome / Q000523:psychology*; D000818:Animals; D015153:Blotting, Western; D018118:Chloride Channels / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000523:psychology; D055724:Electrophysiological Phenomena; D005110:Extracellular Space / Q000187:drug effects; D005239:Fear / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D047468:Immunoprecipitation; D017774:Long-Term Potentiation / Q000187:drug effects*; D008569:Memory Disorders / Q000523:psychology*; D051379:Mice; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000502:physiology; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors*; D018091:Receptors, AMPA / Q000096:biosynthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors
chemical_list: D018118:Chloride Channels; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases