Neurodevelopmental disorder-associated Rho regulators in neocortical development

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ABSTRACT Proper development and function of the neocortex, a brain structure critical for all higher-order functions, relies on the tightly controlled migration of neocortical pyramidal (NP) neurons from their place of birth to their final position in the developing neocortex. Once neurons reach their destination, they further mature and establish functional connections. Significantly, defects in the migration of NP neurons are linked to neurodevelopmental disorders (NDDs) of cognition and epilepsy, highlighting the importance of this process in neocortical development and function. Yet, the molecular mechanisms that govern NP neuron migration and associated brain disorders remain poorly understood. We recently uncovered that the multi-domain containing Rho-GAP oligophrenin-1 (OPHN1) is prominently expressed in NP neurons in the developing neocortex, and, importantly, that it plays a key role in the proper migration and consequent positioning of newborn NP neurons in vivo. Notably, mutations in OPHN1 cause a syndromic form of intellectual disability. Besides learning disabilities, affected individuals typically exhibit epileptic seizures and behavioral/sensory deficits. These findings provide a unique entry point for studying the mechanisms that control NP neuron migration and how such deregulation contributes to common brain disorders. This application aims to define the underlying mechanisms by which OPHN1 governs NP neuron migration, to elucidate how OPHN1 is regulated in such neurons, and to characterize how its loss during embryonic development affects the cytoarchitecture/function of the postnatal/adult mouse neocortex and the behavior of such animals. To this end, Aim 1 will define and characterize the cellular processes and effector pathways OPHN1 impinges on. Our preliminary data suggest that OPHN1 exerts its effects via RhoA-dependent and RhoA-independent pathways, each influencing distinct cellular aspects of NP neuron migration. Therefore, we will delineate the RhoA effector pathway(s) involved and identify novel molecular interactions that mediate OPHN1’s effects on NP neuron migration, using innovative genetic, molecular and cellular tools. Aim 2 will investigate the mechanisms that regulate OPHN1 function in NP neurons, with a particular focus on the BDNF receptor tyrosine kinase TrkB, which we posit to act as key regulator of OPHN1 in NP neuron migration by phosphorylating and consequently activating the protein. To test this, we will employ molecular/cellular tools and genetic strategies to illuminate the mode of OPHN1 regulation by BDNF/TrkB signaling and address its functional importance for NP neuron migration. Aim 3 will apply morphometric and electrophysiological techniques to examine the morphology of NP neurons and neuronal/network activity in neocortices of juvenile/adult NEX- Ophn1cKO mice lacking OPHN1 in postmitotic NP neurons. Furthermore, we will examine the behavior of NEX- Ophn1cKO mice, with a particular focus on sensory-based and social/behavioral responses in addition to seizure susceptibility. Together, our studies will provide novel insight into the mechanisms governing NP neuron migration and shed light on the pathomechanisms contributing to NDDs of cognition and epilepsy.