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Biol Psychiatry. 2017 Feb 1;81(3):193-202. doi: 10.1016/j.biopsych.2016.06.008. Epub 2016 Jun 16.

Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.

Author information

1
Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
2
Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
3
Department of Biology, University of Pennsylvania, Philadelphia.
4
Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
5
Department of Cell Biology, Kansai Medical University, Osaka, Japan.
6
Department of Psychiatry,Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Center for Autism Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
7
Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
8
Institute of Neuroscience and Medicine, Forschungzentrum Julich, Julich; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical School, RWTH Aachen University, Aachen, Germany.
9
Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. Electronic address: ebrodkin@mail.med.upenn.edu.

Abstract

BACKGROUND:

Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.

METHODS:

Mice lacking one copy of Pcdh10 (Pcdh10+/-) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.

RESULTS:

Male Pcdh10+/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10+/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.

CONCLUSIONS:

Our studies reveal that male Pcdh10+/- mice have synaptic and behavioral deficits, and establish Pcdh10+/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.

KEYWORDS:

Amygdala; Autism; Gene; NMDA; Protocadherin; Synapse

Comment in

PMID:
27567313
PMCID:
PMC5161717
DOI:
10.1016/j.biopsych.2016.06.008
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Financial Disclosures Warren Bilker has consulted for Janssen Pharmaceuticals. The consulting is not related to the subject matter of the manuscript. Robert T. Schultz has received consulting fees from Akili Inc, Johnson & Johnson Consumer Inc, and Lumos Pharma Inc. The consulting is not related to the subject matter of the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest.

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