Neuronal firing activity within the cerebral cortex is regulated by a diverse assortment of inhibitory GABAergic interneurons, which are able to finely tune circuit activity through a vast array of morphological, molecular, synaptic, and electrophysiological properties. Intrinsic genetic programs and extrinsic experience- driven learning are both likely to play a role in defining different neuronal subtypes and distributing these cells to layers and regions throughout the brain in the proper density to allow formation of meaningful circuit motifs. To approach a complete understanding of interneuron development, the next challenge is to characterize the entire life history of a bona-fide interneuron subtype such as the chandelier cell, arguably the most distinct and uniform GABAergic interneuron yet to be described. Chandelier cells have an unmistakable axon arbor of hundreds of vertically arranged cartridge synapses, each of which specifically innervates the axon initial segment of a pyramidal cell, the site where action potentials are generated. A single chandelier cell can rapidly impact the firing of large groups of excitatory cells in critical cortical layers, while spcific deficits in chandelier cell boutons occur in the brains of schizophrenia patients, further highlighting their importance. We recently characterized the spatial and temporal origin of chandelier cells in mice, demonstrating that these cells originate in a previously uncharacterized domain bordering the lateral ventricle that we have termed the ventral germinal zone (VGZ). The goal of this proposal is to discover the impact of progenitor cell genetic programs and birth timing on chandelier cell distribution and specification in key regions of the cerebral cortex. We propose to combine cre-dependent reporters with inducible knock-in cre drivers of developmental transcription factors in order to fate map chandelier cells to the amygdala, neocortex, and hippocampus in the developing rodent brain in vivo. Furthermore, we propose to combine cre and flippase lines in genetic intersectional strategies to target neuron-generating cell divisions of radial glial stem cells and intermediate progenitor cells with unprecedented temporal specificity. These experiments will effectively mark chandelier cells at the time of """"""""birth"""""""" and allow the tracking of their trajectory into the cortex, where they are assembled into specific cortical layers. The timing and location of progenitor cell divisions are carefully orchestrated during development, an important process that sets the stage for interneuron-pyramidal cell synapse formation. These approaches will ideally provide an unparalleled example of how a specific type of neuron is produced and appropriately dispatched into the cortex for integration into neuronal circuitry. By studying these events, we hope to begin to understand how disordered neuronal connectivity ultimately manifests as debilitating cognitive and behavioral disturbances in schizophrenia, an illness that afflicts more than 1% of the general population.
Schizophrenia is a prevalent and devastating psychiatric disorder for which the causative genetic and environmental factors are poorly understood. Up to 1.5 million new cases are diagnosed each year in the United States, amounting to billions of dollars-worth of yearly healthcare costs. This can ultimately only be prevented by understanding in detail how individual types of brain cells such as the chandelier cell contribute to disrupted cognitive function in schizophrenia, a pursuit that will ideally aid the development of more effective preventative therapies for patients.
|Kelly, Sean M; Raudales, Ricardo; He, Miao et al. (2018) Radial Glial Lineage Progression and Differential Intermediate Progenitor Amplification Underlie Striatal Compartments and Circuit Organization. Neuron 99:345-361.e4|