Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in angelman syndrome model mice by ErbB inhibitors

Hanoch Kaphzan, Pepe Hernandez, Joo In Jung, Kiriana K. Cowansage, Katrin Deinhardt, Moses V. Chao, Ted Abel, Eric Klann

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)182-190
Number of pages9
JournalBiological Psychiatry
Volume72
Issue number3
DOIs
StatePublished - Aug 1 2012

Fingerprint

Angelman Syndrome
Long-Term Potentiation
Memory Disorders
Fear
Neuregulins
Hippocampus
Schizophrenia
Neuregulin-1
Hippocampal CA1 Region
Neuronal Plasticity
Ligases
Autistic Disorder
Ubiquitin
Intellectual Disability
Epilepsy

Keywords

  • Angelman syndrome
  • ErbB4
  • hippocampus
  • interneurons
  • LTP
  • NRG1

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in angelman syndrome model mice by ErbB inhibitors. / Kaphzan, Hanoch; Hernandez, Pepe; Jung, Joo In; Cowansage, Kiriana K.; Deinhardt, Katrin; Chao, Moses V.; Abel, Ted; Klann, Eric.

In: Biological Psychiatry, Vol. 72, No. 3, 01.08.2012, p. 182-190.

Research output: Contribution to journalArticle

Kaphzan, Hanoch ; Hernandez, Pepe ; Jung, Joo In ; Cowansage, Kiriana K. ; Deinhardt, Katrin ; Chao, Moses V. ; Abel, Ted ; Klann, Eric. / Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in angelman syndrome model mice by ErbB inhibitors. In: Biological Psychiatry. 2012 ; Vol. 72, No. 3. pp. 182-190.
@article{066c736fb362455d9ada0580b3b7e0c6,
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.",
keywords = "Angelman syndrome, ErbB4, hippocampus, interneurons, LTP, NRG1",
author = "Hanoch Kaphzan and Pepe Hernandez and Jung, {Joo In} and Cowansage, {Kiriana K.} and Katrin Deinhardt and Chao, {Moses V.} and Ted Abel and Eric Klann",
year = "2012",
month = "8",
day = "1",
doi = "10.1016/j.biopsych.2012.01.021",
language = "English (US)",
volume = "72",
pages = "182--190",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "3",

}

TY - JOUR

T1 - Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in angelman syndrome model mice by ErbB inhibitors

AU - Kaphzan, Hanoch

AU - Hernandez, Pepe

AU - Jung, Joo In

AU - Cowansage, Kiriana K.

AU - Deinhardt, Katrin

AU - Chao, Moses V.

AU - Abel, Ted

AU - Klann, Eric

PY - 2012/8/1

Y1 - 2012/8/1

N2 - 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.

AB - 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.

KW - Angelman syndrome

KW - ErbB4

KW - hippocampus

KW - interneurons

KW - LTP

KW - NRG1

UR - http://www.scopus.com/inward/record.url?scp=84863677318&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863677318&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2012.01.021

DO - 10.1016/j.biopsych.2012.01.021

M3 - Article

C2 - 22381732

AN - SCOPUS:84863677318

VL - 72

SP - 182

EP - 190

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 3

ER -