High-resolution characterization of functional connectivity and behavior in healthy and transgenic mice from the neonatal period through adulthood

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The development of the brain and its neuronal networks depends on a complex sequence of events during which neurons are born, migrate, arborize, and establish transient or persistent synaptic connections. Alterations in any of these processes can result in neurodevelopmental disorders that persistently affect cognitive functions. The neurodevelopmental hypothesis suggests that neurological disorders such as autism, ADHD, schizophrenia, or epilepsy arise from dysfunctions during early brain development and/or impaired postnatal maturation of the brain. Common causes of neurodevelopmental disorders in humans include birth complications, environmental factors, or genetic disorders. For instance, channelopathies caused by mutations in ion channel genes such as SCN2A or KCNQ2 may cause a range of encephalopathies, both in humans and mice. We have shown that mice lacking KCNQ/Kv7/M-currents exhibit pathological changes in behavior and develop an epilepsy phenotype only when functional M-currents are suppressed during the first two postnatal weeks. This is a key developmental period in rodents, during which spontaneous waves of electrical activity play an important role in brain maturation. Data from animal models and humans suggest that early neuronal activity patterns play an important role in neuronal circuit formation and in the establishment of functional connections between different brain areas. Increasing evidence suggests the presence of altered functional connectivity between prefrontal cortical (PFC) and hippocampal (HPC) regions in cognitive disorders and respective animal models.To be able to follow the process of functional maturation of connectivity in the mouse brain we aim at developing a digital, custom-chip-based recording electrode array using advanced CMOS technology for chronic recordings from freely moving mouse pups and adult mice. This will enable a longitudinal characterization of temporal maturation of PFC and HPC network activities and their functional connectivity in control mice and in mice with altered activities of Kv7/M-, HCN/h-, or SCN2A/Nav1.2-mediated currents.The digital recording array will be used in combination with optogenetic manipulation of GABAergig interneurons to characterize the dynamics of network interaction between PFC and HPC and its changes in our channelopathy mouse models.Furthermore, we will investigate whether attenuation or stimulation of network activity in early brain development will ameliorate the behavioral phenotype in adult mutant mice. Thus, our study will for the first time provide longitudinal data on the dynamics of electrical brain development in channelopathy mouse mutants. The analysis of circuit dynamics in the adult mouse brain of healthy, mutant and mutant mice treated in the neonatal period will lead to a to better understanding of the causal link between early network patterns and delay or impairment in neurobehavioral development.