# The role of RNA binding protein in FXR1P in interneurons

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $425,395

## Abstract

Abstract
Fragile X related protein 1 (FXR1P) is a brain-enriched RNA binding protein. Its loss of function is intolerant for
both mice and humans. Large-scale genome wide association studies and recent gene network analyses have
identified FXR1 as a high confidence risk gene for mental illness. FXR1P has unique protein domains and
mechanisms of action that are distinct from its X-linked homolog fragile X mental retardation protein. Due to
neonatal lethality of FXR1P-null mice the impact of FXR1P deficiency on brain development and postnatal
brain function is largely unexplored. FXR1P is widely expressed in both excitatory and inhibitory neurons in the
mammalian brain throughout postnatal development and in adults. Limited literature and our preliminary data
suggest that FXR1P may have distinct functions in inhibitory versus excitatory neurons. The function of FXR1P
in interneurons has not been studied. Complex neuronal information processing depends on precise spatial
and temporal coordination of principal excitatory neurons, which requires intimate interactions between
excitatory and inhibitory interneurons. Among inhibitory neurons, fast spiking, parvalbumin (PV)-expressing
interneurons (PVIs) have emerged as critical players in many forms of circuit activities. PVIs provide both
feedback and feedforward inhibition to excitatory neurons and entrain cortical networks to drive gamma
oscillations and control their frequency and strength. Extensive studies have shown that gamma oscillations
are important for sensory processing, attention, working memory, and cognition, which are impaired in a
number of mental disorders, including autism and schizophrenia. However, the regulation of gene expression
in PVIs has received limited attention. We found that FXR1P is expressed in a majority of PVIs of adult mouse
cortex. Our preliminary data show that mice with PVI-specific deletion of FXR1P exhibited deficits in behaviors
that require proper function of prefrontal cortex (PFC). Interestingly, these behavioral changes are not found in
mice with FXR1P deletion only in forebrain excitatory neurons. We hypothesize that FXR1P regulates gene
expression in PVIs in the PFC to control PVI excitability, synaptic plasticity, and circuit function and FXR1P
deficiency in PVIs alters cortical circuit activities leading to behavioral deficits. We will determine whether
FXR1P deficiency in PVIs in the PFC leads to deficits in PVI physiology and connectivity, impairs PFC-
dependent behaviors, and changes in specific gene networks. This work brings state-of-art techniques together
in a multidisciplinary approach to investigate how FXR1P deficiency impacts the function of an important type
of interneuron. Our approach provides a potential framework for assessing other potentially important genes
with unclear functions, in PVIs and other genetically defined populations of neurons.

## Key facts

- **NIH application ID:** 10456874
- **Project number:** 5R01MH118827-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Xinyu Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,395
- **Award type:** 5
- **Project period:** 2019-09-24 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456874

## Citation

> US National Institutes of Health, RePORTER application 10456874, The role of RNA binding protein in FXR1P in interneurons (5R01MH118827-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10456874. Licensed CC0.

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