Integration strategies of GABAergic interneuron subtypes in the normal and dysfunctional neonatal cerebral cortex

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Our brains are fundamental to whom we are - governing processes such as learning, memory and language, and central to these actions is a huge array of cells whose diversity has proven to be an obstacle to our understanding of brain function and conversely dysfunction. One approach to resolving this conundrum is to investigate and try and understand the rules that govern the developing brain as this lays the foundation for the amazing processing power of our brains. Yet even at this stage, amongst all nerve cells jostling for position how does an individual nerve cell in the developing brain know where to go and which other nerve cells it should form connections to? After all, failure of certain cell types to do just that often results in dire consequences in terms of behaviour and is thought to underpin several severe neurological conditions including epilepsy, schizophrenia and autism. At present we define two categories of nerve cell in the forebrain: excitatory pyramidal cells and local, inhibitory nerve cells termed interneurons. Although the latter are only a minor component of the total number of cells in the brain, they are critical to normal function. The basis of this proposal is a novel approach reliant on the power of genetics to interrogate the contribution of interneurons to emergent brain activity and dissect when and how they might go wrong in models that replicate some of the molecular deficiencies associated with schizophrenia. The purpose: to gain an understanding of the simple, early brain that will (1) establish a set of rules for the more complex mature brain; (2) provide the foundation for a better understanding of these interneuron-related neurological conditions. This approach has proven hard to pursue in the past due to the dynamic nature of the developing brain and the difficulty in targeting specific cells. To overcome this, we will make use of genes crucial for cell identity. Our recent findings have revealed that the fate of a cell is specified early on in the embryo in response to a genetic code, which acts through a cascade of checkpoints to generate the diversity present in the adult. We have begun to crack this code and are now able to pinpoint where and when interneuron are born. Unfortunately from then on the story is still largely incomplete and we have a limited knowledge of how specific classes of interneuron become functional in the newborn brain. This is important because several neurological conditions such as schizophrenia have been linked to deficits in just one or two cell types. Using the bits of code we already know we can identify the same cells time and time again, target our research more effectively and ask important question as to the role of select interneurons to the developing brain. We have the technology to record from individual cells and relate their activity to that of the surrounding brain regions. We hope to use our strategy to follow certain cells, unravel their contribution to early brain function and reveal how and when these cells are directed to assume a particular role. Our initial data points to a critical window early in postnatal life during which we may be able to intervene using either pharmacological or cell based therapy means to restore a degree of normality to the emergent functional network. By resolving this further we will have the cornerstone to probe the newborn brain in more detail, understand how a simple layer of cells in the embryo matures into the amazingly complex adult brain and perhaps open the door to novel therapeutic interventions that could alleviate a range of neurodevelopmental conditions associated with interneuron deficits.