Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors

H Craig Heller; Ahmad Salehi; Bayarsaikhan Chuluun; Devsmita Das; Bill Lin; Sarah Moghadam; Craig C Garner; Damien Colas

doi:10.1016/j.nlm.2014.10.002

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors

Neurobiol Learn Mem. 2014 Dec:116:162-71. doi: 10.1016/j.nlm.2014.10.002. Epub 2014 Oct 29.

Authors

H Craig Heller¹, Ahmad Salehi², Bayarsaikhan Chuluun³, Devsmita Das², Bill Lin⁴, Sarah Moghadam⁴, Craig C Garner⁵, Damien Colas⁶

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: hcheller@stanford.edu.
² Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
³ Department of Biology, Stanford University, Stanford, CA 94305, USA.
⁴ VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: colas@stanford.edu.

PMID: 25463650
DOI: 10.1016/j.nlm.2014.10.002

Abstract

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.

Keywords: Attention; Eplivanserin; Goal directed behavior; Pentylenetetrazole; Risperidone; SR-46349; Ts1Rhr; Ts65Dn.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognition Disorders / genetics
Cognition Disorders / metabolism
Cognition Disorders / physiopathology*
Disease Models, Animal
Down Syndrome / genetics
Down Syndrome / metabolism
Down Syndrome / physiopathology*
Gene Expression
Mice
Nesting Behavior / drug effects
Nesting Behavior / physiology*
Phenotype
Receptor, Serotonin, 5-HT2A / genetics
Receptor, Serotonin, 5-HT2A / metabolism*
Risperidone / pharmacology
Serotonin 5-HT2 Receptor Antagonists / pharmacology*

Substances

Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Antagonists
Risperidone