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.
FXR1P is enriched in the brain and is critical for development. Although identified as a high confidence risk gene for mental disorders, the function of FXR1P in the mammalian brain is largely unknown. This work will investigate how FXR1P regulates an important type of interneurons that are known to be critical for cognition and are impaired in mental disorders. Using a combination of molecular, physiological, genetic, and behavioral methods, this work will provide novel insight into the fundamental relationship among gene, neural circuit, and behaviors, which is critically important for understanding mental disorders.
