Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period

Abstract

Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time-sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism.

Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder

“…Across all species that exhibit rough-and-tumble play, including humans, males engage in more frequent and more intense physical contact (108). We found that dysregulation of cerebellar PGE2 production during the second postnatal week by either inflammation or NSAID administration impairs later play behavior but only in males (104). Females naturally play less but their level of play activity can still be reduced (109), indicating the sex difference is not a floor effect.…”

“…Too much PGE2 stunts the growth of the dendritic tree, resulting in an overall reduction in excitatory synapses. Inhibition of PGE2 production by COX inhibitors has the opposite effect, an overall sprouting of the dendritic tree and increase in excitatory synapses(104). …”

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…[127]. PGE2 plasma levels increased in autistic patients [132] social behaviour in juvenile males but not females [133].…”

Fever and sickness behavior: Friend or foe?

“…When the pregnant mother is sick, it is unlikely that bacterial or viral molecules directly enter the fetal circulation (except in the case of uterine inflammation); in contrast, the neonate is directly exposed to such molecules after birth. It is also important to recall that PGE 2 , the final effector of fever in the brain is an important signaling molecule in brain development (Dean et al, 2012) and generation of the molecule during a fever could have an impact on developmental trajectories. While there is evidence that some newborn animals do not develop a fever immediately after birth, there is nonetheless an innate immune response to LPS (Bilbo et al, 2005;Pillay et al, 1994;Pittman et al, 1974).…”