Formation of the earliest circuits in the cerebral cortex

Building the brain is like erecting a huge building. The construction requires a dynamic scaffold which is built and modified along with the final permanent structure. During and after the completion of the building, the scaffold has to be dismantled at the right places and at the right time. The subplate, formed by the earliest generated and largely transient cortical neurons, is the developmental scaffold of the cortex of the brain, and disruption of these cells may be the source of many developmental disorders and therefore a fundamental topic to study. Developmental disorders of the cerebral cortical (schizophrenia, autism, attention deficit/hyperactivity disorder, ADHD) and hypoxic injuries around the time of birth (periventricular leucomalacia, PVL) involve cells of the subplate. The Molnar group has been investigating the integration of subplate cells into the intracortical and extracortical circuitry, their neurochemical properties and physiological characteristics over the last 16 years. Just like the building scaffold has to change dynamically during the course of the construction, so does the structure and circuitry formed by subplate cells during development. We aim to characterize gene expression patterns in the subplate throughout the life of a mouse and optimize some of these markers for use on human tissue. For subgroups of subplate cells identified by these markers, we aim to characterize their structure and projection pattern and how they function as part of the complex circuitry that is the mouse brain. These approaches require much specialised skills, which are beyond the scope of a single research group. The proposed collaboration will foster the interactions between a physiology laboratory (Dr Ole Paulsen) and a cellular/molecular and anatomical group and will open opportunities for the initiation of clinical applications in neuro-imaging, psychiatry, and neuropathology.

Cortical circuit formation is a fundamental developmental process underpinning all aspects of complex mammalian behavior later in life. Development of the cortex involves transient, dynamic cortical circuits, which get substantially remodelled according to the interplay between the developmental program and the environment. Subplate constitutes a fascinating transient cortical neuron population. They are amongst the earliest generated neurons of our brain and lay the foundation of our developing cerebral cortex. Since most initial cortical input and output are directed through subplate neurons, understanding how the connectivity and functional integration of subplate develops, how the transient subplate circuits co-exist with the more permanent cortical networks and how regional variation across the cortex is programmed, are issues critical to a broader understanding of cortical function. After subserving these functions, the majority of subplate neurons die and give way to the permanent cortical circuits. The developing brain is particularly vulnerable if these transient circuits are damaged or malfunction. Subplate has been implicated in several brain developmental disorders (childhood epilepsy, schizophrenia, autism and cerebral palsy). The Molnar group made significant contributions to the field of early thalamocortical interactions and more recently to the identification of novel markers and the molecular characterisation of subplate. This has provided a unique opportunity to generate genetic models to both monitor their dynamic integration and modulate their synaptic input and output characteristics. The current proposal builds on the work previously supported by MRC CEG (2004-2009) and aims to use an integrated, coordinated interdisciplinary approach. The program will require substantial commitment, development of new methodologies, establishment and generation of transgenic mice colonies (which the group will share with collaborators), and establishing and maintaining longer-term clinical collaborations. In this proposal we aim to (1) study the integration of subplate neurons into the cortical and extracortical circuitry using reporter gene expressing mouse transgenic lines (including Golli-tau-eGFP, CTGF-GFP, Edg2-GFP); (2) use optogenetic tools to dissect the developmental and mature circuitry, (3) identify and validate further subtype specific markers of these selected groups of subplate neurons; and (4) utilize genetic approaches (Golli-cre) to selectively ablate activity (stop-floxed Kir2.1) or output (conditional Snap25 KO) of subplate during development. The validation of murine subplate markers in human shall be initiated and through clinical collaborations this knowledge will be disseminated to clinicopathological analysis.