M1 circuit dysfunction in MECP2 duplication syndrome

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 DESCRIPTION (provided by applicant): Autism-associated genetic mutations produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Such an imbalance may contribute to the rigid, restricted behavioral repertoire, insistence on sameness, and at times savant-like behavior seen in autism spectrum disorders (ASD). Motor dysfunction is a common and early symptom of ASD. Motor learning and with it the ability to form a new behavioral repertoire is essential for children with ASD in order to socially connect and communicate. These children often have a very restricted movement repertoire and require intensive therapy in order to improve and learn new motor skills. Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that contributes to the maintenance of neural circuit homeostasis through the activity-dependent modulation of gene expression and splicing. Its duplication causes MECP2-duplication syndrome, an 100% penetrant monogenic cause of autism, which leads to progressive intellectual disability, autism, motor dysfunction, spasticity, and epilepsy in males. Mice engineered to overexpress MeCP2 at twice normal levels exhibit a similar neurological phenotype. Remarkably, early in postnatal development these animals exhibit enhanced motor learning and memory (Collins et al., 2004), which over time progresses to motor dysfunction, spasticity and epilepsy. Such enhanced motor learning phenotype is shared across several models of autism, and is studied using rotarod training as a paradigm for consolidation of repetitive motor behaviors (Collins et al., 2004; Kwon et al., 2006; Nakatani et al., 2009; Rothwell et al., 2014). Here, we focus on primary motor cortex (area M1), which is known to contribute to motor learning. We will use chronic, in vivo, 2-photon imaging with the sensitive chronic calcium indicator GCaMP6s to follow dynamic patterns of neuronal activity elicited during locomotion in area M1. The study will start at the pr- symptomatic stage, will include a period of motor skill (rotarod) learning in which mutant animals perform better than littermate controls, and will terminate into the time period of motor regression. Tuning curves relative to the speed of locomotion, pairwise synchrony between different cell types ("functional connectivity") and reliability of firing will be followed during otor skill learning and correlated with performance and motor skill acquisition memory. Mice with selective expression of the MECP2 duplication in pyramidal neurons versus inhibitory interneurons will be characterized behaviorally and studied. Specific aim 1: Study how MECP2-duplication (Tg1) mouse area M1 circuits change during motor learning at the pre-symptomatic stage. Specific aim 2: Follow how MECP2-duplication Tg1 area M1 circuit function changes from the pre-symptomatic to the post-symptomatic stage. We aim to forge a link between patterns of M1 circuit dysfunction and abnormal motor behavior in this model of the MECP2 duplication syndrome.