Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior

Abstract

Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of ADK expression in the adult brain, but differences in the onset of ADK deletion. Specifically, we compared Nestin-Cre^+/-:ADK-flox^fl/fl (ADK^ΔBrain) mice with global loss of ADK in the whole brain, beginning in mid-gestation and persisting for life, with Gfa2-Cre^+/-:ADK-flox^fl/fl (ADK^ΔAstro) mice that have normal ADK expression throughout development, but lose astrocyte-specific ADK-expression in young adulthood. Because ADK-expression in adulthood is generally confined to astrocytes, adult ADK^ΔAstro mice show a similar expression profile of ADK in key areas of the brain related to neuropsychiatric behavior, compared to adult ADK^ΔBrain mice. We sought to determine a neurodevelopmental role of ADK on the expression of psychiatric behaviors in adult male and female mice. Adult ADK^ΔBrain mice showed significant deficits in social memory in males, significant contextual learning impairments in both sexes, and a hyper-responsiveness to amphetamine in males. In contrast, ADK^ΔAstro mice showed normal social memory and contextual learning but hypo-responsiveness to amphetamine in males. Our results demonstrate a key developmental role of ADK in mediating behaviors in adulthood related to neuropsychiatric disease and support the greater prevalence of these disorders among males.

Keywords: Adenosine kinase; Attention deficit hyperactivity disorder; Autism; Brain development; Schizophrenia; Sex differences.