Autism Spectrum Disorder (ASD) and Schizophrenia are neuropsychiatric diseases with origins in development, genetics and the environment. Understanding how environmental influences converge with genetic predispositions during specific developmental windows to create a sensitive period is the key to discovering the etiology of and potential therapeutic treatments for these complex disorders. This proposal explores how a specific environmental influence, inflammation and the medications that treat it, can selectively alter brain development and create vulnerability where none existed. Inflammation during fetal or early life substantially increases the relative risk of developing either Autism or Schizophrenia, but the mechanism(s) and sensitive periods by which inflammation confers this risk remain unknown. Pathologies of the cerebellum are frequently associated with both disorders but an effect of inflammation on this brain region has not been considered. Gender is also a major risk factor, with males at almost four times the risk of Autism or (ASD) and an earlier onset of Schizophrenia with more severe symptoms. Many sex differences in the brain are determined by developmental gonadal hormone exposure. Using the laboratory rat, we propose to explore the novel concept that inflammation during a restricted sensitive period leads to excess prostaglandin E2 (PGE2), a proinflammatory molecule that stimulates aromatase activity and estradiol synthesis locally within the cerebellum. Excessive estradiol stunts the outgrowth of Purkinje neuron dendrites by up regulating GABA synthesis. Conversely, exposure to anti-inflammatory medications such as NSAIDs or acetominophen, has the opposite effect, causing exuberant dendritic sprouting. Ultimately, disruption of the normal course of cerebellar development produces changes in juvenile behaviors such as social play, anxiety and somatosensory sensitivity.
Four specific aims will systematically explore a series of hypotheses by determining;SA#1) the sensitive period for prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#2) the mechanism(s) of prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#3) the effects and mechanism(s) of endogenous and exogenous estradiol on cerebellar Purkinje cell development and SA#4) whether manipulations that impact Purkinje cell development during a sensitive period have consequences for behaviors deemed indicators of behavioral changes associated with autism or schizophrenia. The data generated by these experiments will highlight a previously unexpected source of risk for developmental neuropsychiatric disease, prostaglandins elevated during inflammation and/or the frequently used medications designed to block inflammation.
Among the environmental variables contributing to the relative risk of Autism, Autism Spectrum Disorder and Schizophrenia is inflammation during fetal or early life. Pathologies of the cerebellum are frequently associated with these neuropsychiatric disorders. Understanding how inflammation and the medications taken to treat it impact on the developing cerebellum will provide important mechanistic insight into the origins of these disorders of mental health.
|McCarthy, Margaret M; Arnold, Arthur P; Ball, Gregory F et al. (2012) Sex differences in the brain: the not so inconvenient truth. J Neurosci 32:2241-7|