Role of subplate neurosecretion in early cortical circuit formation

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The developing brain is not simply a smaller version of the adult's, but one that has a completely different composition, connectivity, and logic of processing information. The neuronal circuits in the neonate are set up to interpret neural signals while the construction of the brain is still ongoing, with certain cell populations present only during such formation stages. These early cells and their functions are key components for the eventual maturation of the brain similarly to the dynamic transient scaffolds used for the construction of complex buildings.We have a long-standing interest in studying these early-born cells and their involvement in both the normal and abnormal development of the brain. In particular, we focus on a transient compartment characterized by transient neuronal population and temporary synaptic connections called the subplate. Subplate cells are amongst the first born in the cerebral cortex, they initially represent a large cell group distributed in a zone between the site of neurogenesis and their final destination providing a platform for cortical development. However, these cells are only present during embryonic and early postnatal life and if the cortical development proceeds normally, they die at a particular stage. The transient nature of these cells highlights their importance in the assembly of a fully functional brain as well as their susceptibility to damage. We investigate the consequences of prematurity or perinatal brain damage on these cells, and the consequences of ablating them during the developmental time window for neurosecretion. With previous MRC grant funding during the past fourteen years, we characterised the early connections arriving to the cortex, gene expression patterns in subplate neurons at various developmental stages and also identified molecular markers for transient subplate neurons which now help us in the detailed study of these cells in animal models and in humans. This highlighted that many genes that are active in the subplate encode extracellular proteins. We recently described that subplate cells have the shape and intracellular machinery to secrete such proteins (Kondo et al., 2015). Protein secretation and vesicular release is downregulated following conditional knock-down of SNAP25 in subplate cells. Additionally, we demonstrated that one of these proteins - neuroserpin - is upregulated in a rat model of neonatal hypoxia-ischemia, as well as in normal brains at the peak of cell death. Combined with evidence from the adult stroke literature, this suggests that neuroserpin may play a neuroprotective role.We wish to capitalise on our previous achievements by identifying the role that secretion from subplate cells might play in normal brain development and in perinatal damage, particularly by testing whether neuroserpin can reduce the injury following hypoxia ischemia in mice.Our major objectives are:1. Characterise the timing and expression levels of neuroserpin and other secretory proteins in mice during development and after hypoxia. Study neuroserpin expression (mRNA and protein) in human.2. Prevent secretion from subplate cells by blocking regulated vesicle fusion or by removing subplate cells altogether from early postnatal stages and study the consequences this has on brain development.3. Study the effects of hypoxia in mice after viral delivery of neuroserpin into the brain or in neuroserpin knock-out mice.The outcome of this project will bring fundamental insights into the workings of brain development as well as its susceptibility and response to early brain injury. They will help to establish methods of ensuring healthy brain maturation by developing for the understanding necessary for effective treatments of brain damage after hypoxic ischemia and management of development in premature infants.