Regulation of cerebellar estradiol synthesis and Purkinje cell morphology by prostaglandins: Implications for neurodevelopmental disease

Abstract

Cerebellar pathology occurs in autism and schizophrenia, complex diseases with genetic and environmental origins. The genesis of these diseases is still not understood but inflammation in utero or early in childhood is an important environmental risk factor. Prostaglandin E2 (PGE2) is the key regulator of inflammation and fever, and is potently reduced by COX inhibitors, including over-the-counter medications. However, prostaglandins play other roles in normal physiology. In some brain regions such as the preoptic area, prostaglandins play an important role in normal brain development, creating enduring changes in synaptic patterning. Whether prostaglandins are also important factors in cerebellar development is unknown but worth investigating. Cerebellar development in rats is well studied. We demonstrate that inhibiting prostaglandin production via COX inhibitors increases dendrite length and spine number on Purkinje cells in the rat cerebellum during the early postnatal period, and that the prostaglandin PGE2 decreases markers of dendritic spines in vitro during an equivalent time period. We hypothesized that prostaglandins and estradiol are part of a common pathway in the cerebellum as they are in the preoptic area. We report that that PGE2 stimulates the production of estradiol in the immature cerebellum via an upregulation of the enzyme aromatase, and that treatment with estradiol reduces dendritic growth and synaptogenesis of cerebellar Purkinje cells. Given the effects of prostaglandins during cerebellar development and the cerebellar pathology found in diseases such as autism and schizophrenia, we hypothesized that blocking the normal production of prostaglandins with COX inhibitors would alter social behavior and sensory perception, and would lead to enduring alterations in cerebellar morphology. We found a reduction in cerebellar synapses and overall volume in juvenile rats. This later phase is associated with reduced social play behavior and heightened somatosensory response in males alone, a behavioral pattern reminiscent of patients with autism or schizophrenia. We conclude that prostaglandins are important players in cerebellar development and in the development of normal social and sensory behavior. Understanding the role prostaglandins play in development may give us insight into complex human neurodevelopmental diseases.