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.
Key Words
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Article info
Publication history
Published online: March 02, 2012
Accepted:
January 20,
2012
Received in revised form:
January 20,
2012
Received:
October 13,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- The Social Life of Neurons: Synaptic Communication Deficits as a Common Denominator of Autism, Schizophrenia, and Other Cognitive DisordersBiological PsychiatryVol. 72Issue 3
- PreviewAutism and autism spectrum disorders such as Angelman syndrome, affect the ability to successfully integrate and participate in social interactions or to understand social exchanges between others. Ongoing interdisciplinary research aims to identify genetic, molecular, and neurophysiologic causes of autistic phenotypes. Multiple lines of evidence from different disciplines are intersecting at the synapse, the site of chemical communication between neurons and also believed to be the key site of learning in the brain.
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