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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Riddle, Robert D
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Mayer, Christian; Hafemeister, Christoph; Bandler, Rachel C et al. (2018) Developmental diversification of cortical inhibitory interneurons. Nature 555:457-462
Priya, Rashi; Paredes, Mercedes Francisca; Karayannis, Theofanis et al. (2018) Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism. Cell Rep 22:1695-1709
Godbole, Geeta; Shetty, Ashwin S; Roy, Achira et al. (2018) Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon. Development 145:
Bandler, Rachel C; Mayer, Christian; Fishell, Gord (2017) Cortical interneuron specification: the juncture of genes, time and geometry. Curr Opin Neurobiol 42:17-24
Quattrocolo, Giulia; Fishell, Gord; Petros, Timothy J (2017) Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation. Cell Rep 21:721-731
Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J et al. (2016) Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. Neuron 89:521-35
McKenzie, Melissa; Fishell, Gord (2016) Human brains teach us a surprising lesson. Science 354:38-39
Mayer, Christian; Bandler, Rachel C; Fishell, Gord (2016) Lineage Is a Poor Predictor of Interneuron Positioning within the Forebrain. Neuron 92:45-51
Miyoshi, Goichi; Young, Allison; Petros, Timothy et al. (2015) Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons. J Neurosci 35:12869-89
Mayer, Christian; Jaglin, Xavier H; Cobbs, Lucy V et al. (2015) Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries. Neuron 87:989-98

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