The goal of this proposal is to understand the molecular mechanisms by which distinct subtypes of excitatory projection neurons of the neocortex govern the laminar distribution of their interneuron partners, and to define whether acquisition of projection neuron subtype-specific identity is necessary for proper connectivity with local interneurons. The work aims at understanding the contribution of different classes of projection neurons to the establishment of balanced cortical microcircuitry. High-level neocortical function including cognition, sensory perception and motor function relies on the coordinated assembly of a local microcircuitry among an astonishing diversity of excitatory projection neurons and inhibitory interneurons. Indeed, disgenesis and/or disfunction of the local microcircuitry is associated with epilepsy, psychiatric disease and neurodevelopmental disorders [1-3]. The developmental events governing the integration of projection neurons and interneurons into balanced circuitry are poorly understood. We have reported on the central role played by projection neurons in governing this process and the precision by which different subtypes of projection neurons uniquely and differentially determine the laminar distribution of distinct classes of cortical interneurons [4]. We found that absence of subcerebral projection neurons from the neocortex of Fezf2 null-mutant mice and their replacement by commissural projection neurons cause abnormal lamination of interneurons and altered GABAergic inhibition. In agreement, experimental generation of either subcerebral projection neurons or callosal neurons in proximity to the cortex is sufficient to recruit cortical interneurons to these ectopic locations, with class-specificity. The data demonstrate that individual populations of projection neurons cell-extrinsically control the laminar fate of specific interneuron classes with striking precision. This suggests the existence of a "molecular code" that governs the specific interaction between projection neuron and interneuron partners during assembly of the local circuitry. Here, we build on this published work, as well as our recent demonstration that the identity of postmitotic projection neurons can be "reprogrammed" from one subtype into another in vivo [5] to answer the following questions: 1) Is there a "molecular code" enabling subtype-specific interactions among classes of projection neurons and interneurons to guide interneuron lamination? What are the molecules involved? (Aim 1) 2) Are "codes" of cadherin family members involved in establishing proper interneuron lamination? (Aim 2) 3) Is the acquisition of projection neuron subtype-specific identity necessary for the establishment of balanced circuitry/connectivity with interneuron partners? Does the inhibitory input by specific classes of interneurons change upon a change in projection neuron class-specific identity? (Aim 3) We present substantial published and pilot data supporting the significance and feasibility of this work.

Public Health Relevance

We propose to investigate the role played by the different classes of cortical projection neurons over the lamination and integration into circuitry of local inhibitory interneurons. The work aims to understand how normal cortical microcircuitry develops and has the potential to positively inform studies that manipulate the microcircuitry for therapeutic benefit.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Harvard University
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Lodato, Simona; Molyneaux, Bradley J; Zuccaro, Emanuela et al. (2014) Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat Neurosci 17:1046-54
Tomassy, Giulio Srubek; Berger, Daniel R; Chen, Hsu-Hsin et al. (2014) Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 344:319-24
Arlotta, Paola; Berninger, Benedikt (2014) Brains in metamorphosis: reprogramming cell identity within the central nervous system. Curr Opin Neurobiol 27:208-14