Mice Genetically Depleted of Brain Serotonin Display Social Impairments, Communication Deficits and Repetitive Behaviors: Possible Relevance to Autism

Abstract

Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2−/−) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2−/− mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

“…TPH2 KO mice). These mice dig intensely in the absence of any objects in the test cage 16 and a similar situation could occur in other genetically modified mice or in subjects treated with certain drugs. Thus, it is likely that marbles are buried and subsequently uncovered, to be scored inaccurately as unburied.…”

“…As a result of the null mutation in the gene for TPH2, these mice have no measureable brain 5HT 15,16,18 . These mice show a very interesting behavioral phenotype characterized primarily by repetitive, compulsive-like digging and burying 15,16 . Figure 1B shows a representative cage from WT mice and Figure 1C is a cage from a TPH2 knockout (KO) mouse after burying.…”

“…In general, these established models can be classified as genetic, pharmacological, neurodevelopmental and behavioral and most show good face, construct and predictive validity 6,7 . We have used two behavioral models-marble burying and nestlet shredding-to assess repetitive behaviors in mice genetically depleted of serotonin 15,16 . These methods have numerous advantages not the least of which are their ease of use, the accuracy with which the behaviors can be scored, the spontaneous exhibition of these behaviors in rodents, and their use in high-throughput screening of genetically modified mice for abnormal behavioral phenotypes.…”

Transgenic Animal Models for Brain 5-HT Deficiency: An Editorial Summary

“…• Substantial deficits in numerous validated tests of social interaction and communication; highly repetitive and compulsive behaviors; Newborn mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood [23].…”

Biochemical and Neurobiological Study of Moroccan Autists

“…However, the exact mechanism by which genes are implicated in autism is unclear [4]. Other findings suggest that some neuroanatomical impairments in brain areas and/or brain chemistry changing could be involved in this neuropathology [5,6].…”