Aberrant parvalbumin-positive interneuron regulation of maternal behavior in a Rett Syndrome mouse model

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PROJECT SUMMARY/ABSTRACT Rett Syndrome (RTT) is caused by heterozygous loss of function mutations to the gene that encodes methyl CpG-binding protein 2 (MeCP2). Amongst other deficits, RTT results in failure of the brain to activate plasticity programs during times that call for experience dependent learning. For instance, female mice in a RTT mouse model (MeCP2-hets) fail to learn a maternal behavior that relies on auditory processing of newborn pup vocalizations. Pups emit ultrasonic vocalizations when they are separated from the nest which cues maternal retrieval - a learned response to these distress cries. Over the course of that learning process, neural responses in the auditory cortex (AC) of maternally experienced females become more tuned to these newly-relevant, social cues. Not only do MeCP2-hets fail to learn this retrieval behavior, but they also exhibit parvalbumin (PV) inhibitory interneuron abnormalities in the AC specific to this period of experience-dependent plasticity. Prior characterizations of these PV aberrations point towards a hyperactive and hypermature AC PV network in the RTT model during this period, likely reflecting insufficient plasticity for the retrieval behavior to be successfully learned. However, technical limitations of these studies have only provided static snapshots of AC PV network properties at timepoints with relevance to the onset of maternal experience; this has impeded our understanding of the real-time AC PV network contributions to retrieval, and the direct behavioral consequences of its dysregulation in MeCP2-hets. Therefore, this project aims to determine the role of AC PV neurons in regulating maternal pup retrieval, and reveal how specific disruptions to the AC PV network impair this behavior in real time. Aim 1 will use fiber photometry and computational modeling to test the hypothesis that the AC PV network dynamically regulates retrieval, and network dysregulation in MeCP2-hets results in retrieval deficits. Aim 2 will employ optogenetics to test the hypothesis that suppressing the erroneously strengthened AC PV network in the RTT model will rescue performance of the retrieval behavior. Together, this work will reveal novel insight into the cellular and network-level bases of plasticity deficits that characterize many neurodevelopmental disorders, and validate a potential cellular therapeutic target for RTT patients. Cold Spring Harbor Laboratory (CSHL) is a world-renowned, vibrant, and collaborative environment to carry out the proposed research. Apart from being home to several highly respected neuroscience laboratories, the CSHL Meetings and Courses Program provides myriad opportunities to interact with world renowned scientists and trainees that regularly visit campus. This unparalleled exposure will strengthen my professional network and facilitate future collaborations in the next stages of my scientific career. Additionally, my comprehensive and diverse mentoring network will support my scientific growth in this fellowship through a training plan that emphasizes critical thinking and technical skill development, scientific communication, outreach and leadership.