# Prostaglandins and Cerebellum Development

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $386,250

## Abstract

Pathologies of the cerebellum are leading contributors to social, communicative, cognitive and affective
deficits associated with neuropsychiatric disorders with origins in development. These include autism
spectrum disorders, attention deficit and hyperactivity and early onset schizophrenia. Neuroinflammation
early in life is a leading environmental risk for these disorders and being male is a leading biological
predictor. Using the laboratory rat we have identified a previously unknown sensitive period in cerebellar
development that involves an intrinsic gene expression profile that creates a vulnerability to dysregulation
by inflammation. Specifically, in the healthy cerebellum the prostaglandin PGE2 stimulates the aromatase
enzyme leading to increased estradiol production and regulation of the growth of Purkinje neurons. The
2nd postnatal week is a sensitive period and perturbation of this pathway during that time impairs Purkinje
neuron development and results in long-term behavioral deficits revealed by assays of social play,
cognition and somatosensory thresholds. For reasons that are not understood, behavioral deficits are
greater in males. The sensitive period is defined by a peak in expression of both the gene coding for
aromatase (Cyp19a) and the estrogen receptor (Esr1) during the 2nd postnatal week. Microglia are the
brains innate immune cells and we also find that “semi-activated” microglia peak during the 2nd postnatal
week in the healthy cerebellum. Microglia both respond to and produce PGE2, creating a positive
feedback loop. Initial findings suggest that an inflammatory insult during the sensitive period induces
enduring inflammation that is detectable until at least late adolescence, leading to our overarching
hypothesis: Inflammation during the sensitive period generates enduring inflammation that is
mediated by over active microglia and alters the developmental trajectory of the cerebellum. Pilot
data suggests enduring inflammation is more severe in males. Therefore we further hypothesize that
behavioral changes in males are secondary to enduring inflammation. We will test these
hypotheses in SA1 with a comprehensive characterization of enduring inflammation in both sexes. In SA2
we determine the role of microglia in both establishing and maintaining enduring inflammation. SA3
explores the epigenetic underpinnings of enduring inflammation at the candidate gene level and the
genome-wide methylome of microglia. The final aim, SA4, determines whether the greater vulnerability of
males is encoded by earlier hormonally-mediated sexual differentiation of the brain. Therapeutic
interventions that either stop the establishment of or reverse the maintenance of enduring inflammation
are explored in multiple aims and offer a clear path towards future translation to humans.

## Key facts

- **NIH application ID:** 9926725
- **Project number:** 5R01MH091424-10
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MARGARET M. MCCARTHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2010-07-23 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926725

## Citation

> US National Institutes of Health, RePORTER application 9926725, Prostaglandins and Cerebellum Development (5R01MH091424-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926725. Licensed CC0.

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