Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests

Abstract

Accelerated head and brain growth (macrocephaly) during development is a replicated biological finding in a subset of individuals with autism spectrum disorder (ASD). However, the relationship between brain overgrowth and the behavioral and cognitive symptoms of ASD is poorly understood. The PI3K-Akt-mTOR pathway regulates cellular growth; several genes encoding negative regulators of this pathway are ASD risk factors, including PTEN. Mutations in PTEN have been reported in individuals with ASD and macrocephaly. We report that brain overgrowth is widespread in Pten germline haploinsufficient (Pten(+/-)) mice, reflecting Pten mRNA expression in the developing brain. We then ask if broad brain overgrowth translates into general or specific effects on the development of behavior and cognition by testing Pten(+/-) mice using assays relevant to ASD and comorbidities. Deficits in social behavior were observed in both sexes. Males also showed abnormalities related to repetitive behavior and mood/anxiety. Females exhibited circadian activity and emotional learning phenotypes. Widespread brain overgrowth together with selective behavioral impairments in Pten(+/-) mice raises the possibility that most brain areas and constituent cell types adapt to an altered trajectory of growth with minimal impact on the behaviors tested in our battery; however, select areas/cell types relevant to social behavior are more vulnerable or less adaptable, thus resulting in social deficits. Probing dopaminergic neurons as a candidate vulnerable cell type, we found social behavioral impairments in mice with Pten conditionally inactivated in dopaminergic neurons that are consistent with the possibility that desynchronized growth in key cell types may contribute to ASD endophenotypes.

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…The Pten m3m4 model also demonstrated poor balance on the accelerating rotarod task, potentially in keeping with the motor clumsiness reported in individuals with high-functioning ASD [61,89]. Finally, altered circadian rhythms are noted in ASD, and are also reported in the Nse-cre; Pten loxP/loxP model as disturbed free-running rhythm and lower overall circadian activity in female Pten +/-mice [84,86].…”

“…Although their phenotypes are an imperfect match, the germline heterozygous Pten +/-mouse is the closest available model for patients with PHTS with PTEN alterations that lead to low protein dose, such as nonsense mutations or frameshift causing insertions/deletions [9]. Several studies give a thorough description of social and other ASD-linked behaviors in these animals [84,85,88], finding lower overall sociability and a number of sex-specific phenotypes. Most recently, our group identified inappropriately elevated social behavior in male Pten m3m4 mice, where Pten localization is altered similarly to that seen in some PHTS missense mutations [57,61].…”

“…In addition to social behavior deficits, several mouse models of Pten loss exhibit behaviors relevant to other core symptoms of ASD or frequent comorbidities. Repetitive behaviors, now a critical half of ASD diagnosis, are seen in Gfap-Cre; Pten loxP/loxP and male Pten +/-animals as repetitive marble burying or selfgrooming [84,87]. Although epilepsy is not part of Cre-lox = Cre-loxP-mediated recombination; NA = not applicable the diagnostic criteria for ASD, its association with germline PTEN mutations in several recent case reports adds new relevance to the seizure phenotypes observed in multiple mouse models of neural Pten loss [30-33, 62, 86].…”

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Social behavior assays have been conducted with many of the mouse models in which imaging studies were conducted. Employing our 3-chambered social approach task, a simple yes-or-no assay for sociability [13], absence of sociability was reported in mice with mutations in genes including Shank3 [15,16], Cntnap2 [17], Pten [18], Tsc1 [19], En2 [20], Gabrb3 [21], Ube3a triplication [22], and oxytocin receptor knockouts [23]. Normal 3-chambered social approach appeared in mice with mutations in genes including oxytocin [24], Shank1 [25], Nlgn2 [26], Ephrin-A [27] and 16p11.2 deletion [28] Variable findings on social approach across laboratories and in mouse lines generated on different genetic backgrounds have been reported for mutations including Fmr1 [29,30], Nlgn3 [31][32][33][34], and Nlgn4 [35,36].…”

Autism Spectrum Disorders: Translating human deficits into mouse behavior

“…Several ASD mouse models present deficits in this task. Specifically, reduced reciprocal interaction and a delay to engage the first contact were reported (Clipperton-Allen and Page, 2014;Santini et al, 2013;Schmeisser et al, 2012;Tabuchi et al, 2007;Zhou et al, 2009).…”