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  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    335—Rett's Syndrome and Other Genetic Developmental Disorders

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    335.12: Impaired learned maternal behavior in a mouse model of Rett Syndrome

    Location: Halls B-H

    *B. Y. LAU, K. KRISHNAN, G. EWALL, Z. HUANG, S. SHEA;
    Cold Spring Harbor Labs., Cold Spring Harbor, NY

    Abstract Body: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2). In RTT, as in many autism spectrum disorders (ASDs), patients exhibit difficulty with perceiving communicative gestures including spoken language. The mechanisms by which MeCP2 mutations lead to defects in the neural circuitry that enables vocal perception are unknown. In contrast to wild type virgin female mice, wild type mother mice readily retrieve scattered newborn pups. It is believed that this behavior is motivated by perception of distress vocalizations emitted by the pups, and is enabled by auditory cortical plasticity driven by maternal experience. We developed a behavioral assay in which virgin wild-type females were designated maternal apprentices by being placed in a cage with a pregnant mother prior to parturition. Wild type (MeCP2+/+) apprentices showed gradual improvement in retrieval behavior over the course of several days. However, heterozygous MeCP2 +/- mutant females (MeCP2-het) failed to develop proficiency at the pup retrieval behavior and frequently abandoned pups after interacting. This latter behavior was rarely observed in WT apprentices or mothers. Taken together with our recent work showing that MeCP2 regulates critical period timing in the visual system, we propose that this function may generalize to other regions and developmental time points, and may have behavioral consequences. We are currently assessing the effects of perturbing MeCP2 expression exclusively in the auditory cortex, and recordings from individual neurons in the auditory cortex of awake, behaving MeCP2-het mice are ongoing.
    Note: B. Y. Lau and K. Krishnan contributed equal work.

    Lay Language Summary: We report that female mice carrying a genetic mutation that causes Rett syndrome in humans are impaired in their ability to learn maternal behaviors and care for pups. Proper maternal care requires a mother mouse to hear and respond to her pups’ distress calls, and maternal learning actually changes the way the auditory cortex processes pup vocalizations. We believe the inability to properly respond to pup calls parallels language impairments in Rett syndrome. By uncovering the basis for altered auditory cortex plasticity and impaired pup retrieval in the Rett mutant mouse model, we hope to explain how a genetic mutation can lead to communication impairments.
    Autism spectrum disorders such as Rett syndrome are often marked by difficulty producing and perceiving language. Our study presents a new behavioral approach to exploring the neural basis of this symptom using mice with a genetic defect that matches the one in girls with Rett syndrome more closely than many other studies. Moreover, by using a mouse model, we are able to relate poor performance of maternal behavior to altered inhibitory processing in the brain's auditory system.
    We used a behavioral assay that measures the mouse's efficiency and accuracy for retrieving stray pups and gathering them in the nest. This behavior seems to crucially rely on the mouse’s ability to perceive distress calls made by the pups when they are separated from the nest. Female mice with no maternal experience are not proficient at this behavior, but pup gathering skills can be acquired by learning from a seasoned mother mouse. We compared the ability of female Rett syndrome mutant mice to learn gathering with that of control mice that lacked the mutation. When apprenticed to an experienced mother mouse, control female mice with no prior maternal experience were able to acquire maternal care skills. In contrast, mutant females exhibited much poorer performance and failed to improve, even after five days living with a mother and her pups.
    Previous studies revealed that this maternal learning is accompanied by changes to inhibitory processing of distress calls in the auditory cortex. Inhibitory signaling in the auditory cortex shapes neural activity, helping tune it to the frequency range of pup calls. We recorded neuronal responses to sounds (including pup calls) in the auditory cortex of awake female mice, comparing mutants and controls with and without maternal experience. Mutant mice showed evidence of dysregulated inhibitory responses to sound including pup calls.
    Based on these observations, our working hypothesis is that behavioral deficits evident in mutant mice are in part due to improper control of inhibitory neural plasticity in the auditory cortex. We are currently exploring the molecular and neural circuit mechanisms of our behavioral results.
    We believe that our results put forward a valuable new approach to studying the circuit and molecular bases of communication difficulties in Rett syndrome. A key feature of this approach is our ability to directly relate neural pathology to a simple, robust and innate behavior. This model system can be used to test the hypothesis that neural plasticity and sensory activity related to vocal perception are a factor causing communication deficits in humans with Rett syndrome.