The complex functions of the cerebral cortex rely on a widely distributed but highly connected networks of excitatory pyramidal and stellate neurons, integrated together by a diverse population of GABAergic cortical interneurons. Over the past decade, we have studied the origin and genetic factors that shape the development of cortical interneurons using the barrel cortex as a well-characterized model to investigate the mechanisms underlying the emergence of cortical interneuron diversity. In this proposal, we will specifically focus on the development of somatostatin-expressing cortical interneurons within this region of the neocortex. As shown in our preliminary studies, this population of cortical interneurons is the first to be born and appear to have a unique role in establishing cortical network activity. They achieve this function by forming both transient and precocious afferent and efferent connections, thus linking nascent ascending sensory information with cortical network activity. In this proposal we will both investigate the developmental events by which this population achieves its mature connectivity and examine how these cells contribute to the establishment of cortical architecture. Moreover, we will explore how the transcription factor Satb1 which is selectively expressed with somatostatin-expressing cortical interneurons is required for the maturation of this population. Our preliminary analysis has revealed that the expression of the gene encoding the Satb1 protein is regulated by activity suggesting that it acts as a direct link between early network activity within the cortex and the genetic program directing the development of this cell type. As such, we will also explore the phenotype resulting from perturbations in the normal excitatory drive impinging on this cell type. Together, this proposal will not only contribute to our understanding of the maturation of this cell type but help in clarifying how cortical architecture is established. Clinical Relevance: Although the present experiments are focused at a basic level on early events involved in cortical development, a growing body of evidence suggests that developmental perturbations in cortical interneuron populations results in a variety of affective brain disorders, including schizophrenia, epilepsy and ASD. Although Satb1 mutations have at least as yet not been implicated a risk gene for these disorders, both Satb1 null mice and the conditional removal of Satb1 in cINs result in behavioral abnormalities including hind- limb clasping reflex and interictal epileptiform seizure activity, particularly during sleep. It thus seems extremely likely that findings from these studie will have direct bearing on our understanding of the etiology of affective neurological disorders and their relationship to aberrant cortical development.
In this proposal, we use a combination of genetics, imaging and physiology to study the role somatostatin cortical interneurons (SST-cINs) play in the development of cortical networks. As shown in our preliminary studies, SST-cINs appear to transit through a critical period during which they both receive and form widespread synaptic connections. Through this it appears that SST-cINs play a previously unsuspected role in the establishment of network activity. In addition to describing these unanticipated developmental events, we examine the contribution of a novel transcription factor Satb1 that is essential for the development of this interneuron population. Finally, we explore the role of activity in both shaping the development of this population and by proxy the emergence of cortical network function.
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|McKenzie, Melissa; Fishell, Gord (2016) Human brains teach us a surprising lesson. Science 354:38-39|
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|Tuncdemir, Sebnem N; Fishell, Gord; Batista-Brito, Renata (2015) miRNAs are Essential for the Survival and Maturation of Cortical Interneurons. Cereb Cortex 25:1842-57|
|Kepecs, Adam; Fishell, Gordon (2014) Interneuron cell types are fit to function. Nature 505:318-26|
|De Marco Garcia, Natalia V; Fishell, Gord (2014) Subtype-selective electroporation of cortical interneurons. J Vis Exp :e51518|
|Cassataro, Daniela; Bergfeldt, Daniella; Malekian, Cariz et al. (2014) Reverse pharmacogenetic modulation of the nucleus accumbens reduces ethanol consumption in a limited access paradigm. Neuropsychopharmacology 39:283-90|
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