Knockdown of the Non-canonical Wnt Gene Prickle2 Leads to Cerebellar Purkinje Cell Abnormalities While Cerebellar-Mediated Behaviors Remain Intact.

Autism spectrum disorders (ASD) involve brain wide abnormalities that contribute to a constellation of symptoms including behavioral inflexibility, cognitive dysfunction, learning impairments, altered social interactions, and perceptive time difficulties. Although a single genetic variation does not cause ASD, genetic variations such as one involving a non-canonical Wnt signaling gene, Prickle2, has been found in individuals with ASD. Previous work looking into phenotypes of Prickle2 knock-out (Prickle2-/-) and heterozygous mice (Prickle2-/+) suggest patterns of behavior similar to individuals with ASD including altered social interaction and behavioral inflexibility. Growing evidence implicates the cerebellum in ASD. As Prickle2 is expressed in the cerebellum, this animal model presents a unique opportunity to investigate the cerebellar contribution to autism-like phenotypes. Here, we explore cerebellar structural and physiological abnormalities in animals with Prickle2 knockdown using immunohistochemistry, whole-cell patch clamp electrophysiology, and several cerebellar-associated motor and timing tasks, including interval timing and eyeblink conditioning. Histologically, Prickle2-/- mice have significantly more empty spaces or gaps between Purkinje cells in the posterior lobules and a decreased propensity for Purkinje cells to fire action potentials. These structural cerebellar abnormalities did not impair cerebellar-associated behaviors as eyeblink conditioning and interval timing remained intact. Therefore, although Prickle-/- mice show classic phenotypes of ASD, they do not recapitulate the involvement of the adult cerebellum and may not represent the pathophysiological heterogeneity of the disorder.

Prenatal stress and genetic risk: How prenatal stress interacts with genetics to alter risk for psychiatric illness.

Risk for neuropsychiatric disorders is complex and includes an individual's internal genetic endowment and their environmental experiences and exposures. Embryonic development captures a particularly complex period, in which genetic and environmental factors can interact to contribute to risk. These environmental factors are incorporated differently into the embryonic brain than postnatal one. Here, we comprehensively review the human and animal model literature for studies that assess the interaction between genetic risks and one particular environmental exposure with strong and complex associations with neuropsychiatric outcomes-prenatal maternal stress. Gene-environment interaction has been demonstrated for stress occurring during childhood, adolescence, and adulthood. Additional work demonstrates that prenatal stress risk may be similarly complex. Animal model studies have begun to address some underlying mechanisms, including particular maternal or fetal genetic susceptibilities that interact with stress exposure and those that do not. More specifically, the genetic underpinnings of serotonin and dopamine signaling and stress physiology mechanisms have been shown to be particularly relevant to social, attentional, and internalizing behavioral changes, while other genetic factors have not, including some growth factor and hormone-related genes. Interactions have reflected both the diathesis-stress and differential susceptibility models. Maternal genetic factors have received less attention than those in offspring, but strongly modulate impacts of prenatal stress. Priorities for future research are investigating maternal response to distinct forms of stress and developing whole-genome methods to examine the contributions of genetic variants of both mothers and offspring, particularly including genes involved in neurodevelopment. This is a burgeoning field of research that will ultimately contribute not only to a broad understanding of psychiatric pathophysiology but also to efforts for personalized medicine.