Pagliaro, Alexa H (May 2023) A disrupted parvalbumin network state impairs maternal behavior in a mouse model of Rett Syndrome. PhD thesis, Cold Spring Harbor Laboratory.
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Abstract
Rett Syndrome is a neurodevelopmental disorder caused by heterozygous loss of function mutations to the gene that encodes methyl CpG-binding protein 2 (MeCP2) – a ubiquitously expressed transcription factor. Amongst other deficits, Rett Syndrome results in a failure of the brain to activate plasticity programs during times that call for experience dependent learning. The onset of maternal experience is an ideal time to experimentally probe such plasticity mechanisms in adulthood, as this period reflects a time of great learning demands within an ethologically relevant context. Consistent with an inability to activate plasticity programs, female mice in a Rett Syndrome mouse model (MeCP2hets) 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 litter which prompts maternally experienced females to find and retrieve the pups back to the nest. MeCP2hets not only fail to learn this retrieval behavior, but they also exhibit parvalbumin inhibitory interneuron (PV) abnormalities in the auditory cortex (ACtx) during this period of experience-dependent plasticity. Aberrations specific to the PV network are particularly intriguing given this neural subpopulation’s well-documented role in regulating critical periods for plasticity. Previous characterizations of the PV abnormalities in MeCP2hets point towards a hyperactive and hypermature ACtx PV network, likely reflecting insufficient plasticity for the retrieval behavior to be successfully learned. However, technical limitations of these studies have only provided snapshots of the ACtx PV network at timepoints with relevance to the onset of maternal experience; this has impeded our understanding of the real-time ACtx PV network 15 contributions to retrieval, and the direct behavioral consequences of its dysregulation in MeCP2hets. To overcome these limitations, we have monitored ACtx PV activity during retrieval behavior over the course of the postnatal period. Our results provide hitherto unequaled insight into ACtx PV dynamics in freely behaving animals, and a cell-type specific network underlying adult experience-dependent plasticity. Through these experiments, we uncovered a characteristic low frequency ACtx PV activity pattern in wild type females that was notably absent in MeCP2hets. The low frequency fluctuations reflected both sensory and behavioral information during retrieval assays, but together these events only accounted for a small proportion of the overall signal dynamism. This prompted us to consider that the low frequency fluctuations were more indicative of a plasticity-conducive PV network state, which was supported by the discovery that the ACtx PV activity was tightly coupled with pupil size (an established proxy for attention and arousal). In an effort to induce this ACtx PV network state in MeCP2hets, we showed that chronic, but not acute, chemogenetic ACtx PV inhibition rescued retrieval performance. Not only did this manipulation improve behavior, but it also disassembled perineuronal nets around PV cells (perineuronal nets typically act as blockades to synaptic plasticity), and induced the emergence of modest low frequency ACtx PV fluctuations in MeCP2hets. Taken together, we propose that the low frequency ACtx PV fluctuations are a signature of a PV network state that is prepared to meet plasticity demands in adulthood.
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