The functions of the cerebral cortex depend on highly interconnected and dynamic microcircuits composed of two types of neurons, glutamatergic excitatory neurons that propagate the signals through the various stages of processing and GABAergic interneurons (INs) that regulate this information flow and sculpt cortical circuits. Signal processing in the cortex depends critically on the activity of these interneurons. This Program Project is focused on the characterization of a population of GABAergic INs whose size and breadth have been previously underestimated. These INs express the ionotropic serotonin receptor 5HT3a and largely originate during development from the caudal ganglionic eminence (CGE). Preliminary studies show that 5HT3aR INs represent about 30% of the total IN population in somatosensory cortex, and that they are concentrated in superficial layers, where they represent the largest IN population. This suggests that they are important in the processing of information in the associative layers of cortex. 5HT3aR INs are heterogeneous, but they are uniformly and potently modulated by serotonin and acetylcholine via ionotropic receptors. The Program Project will investigate the roles of cortical 5HT3aR INs on the development and function of the cerebral cortex. The PPG will consist of three research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. Project I (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR INs population. It will investigate the genetic program that governs the differentiation of 5HT3aR INs precursors, their connectivity throughout development and the role of activity on their maturation in the cortex. Project II (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR INs in cortical function. Specifically, it will test the hypothesis that they are important in context-dependent sensory processing. It will investigate the functional connectivity of 5HT3aR INs, use photostimulation of channelrhodopsin-expressing cholinergic and serotonergic axons to investigate their modulation by these subcortical inputs and two photon targeted recordings in vivo to investigate the activity of 5HT3aR INs during different behavioral states and their response to motor activity and sensory stimulation. Project III (by Wen-Biao Gan) will investigate the location, structure and plasticity of the synapses 5HT3aR INs make on layer V pyramidal neurons and the role of these INs in regulating the activity and structural dynamics of pyramidal cells during learning and memory formation.

Public Health Relevance

Recent work from numerous sources suggests that dysfunction of cortical INs is a proximal cause for numerous neurological disorders including schizophrenia, epilepsy, and autism spectral disorders. Given the known role of serotonin and acetylcholine in attention, learning, and anxiety, our recent discovery that the INs we are studying are modulated by these neuroligands suggests these populations are a particularly good target for understanding the etiology of these disorders and developing treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Schools of Medicine
New York
United States
Zip Code
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
Tremblay, Robin; Lee, Soohyun; Rudy, Bernardo (2016) GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits. Neuron 91:260-92
Ma, Lei; Qiao, Qian; Tsai, Jin-Wu et al. (2016) Experience-dependent plasticity of dendritic spines of layer 2/3 pyramidal neurons in the mouse cortex. Dev Neurobiol 76:277-86
Qiao, Qian; Ma, Lei; Li, Wei et al. (2016) Long-term stability of axonal boutons in the mouse barrel cortex. Dev Neurobiol 76:252-61
Petros, Timothy J; Bultje, Ronald S; Ross, M Elizabeth et al. (2015) Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate. Cell Rep 13:1090-5
Cichon, Joseph; Gan, Wen-Biao (2015) Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity. Nature 520:180-5
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
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
De Marco García, Natalia V; Priya, Rashi; Tuncdemir, Sebnem N et al. (2015) Sensory inputs control the integration of neurogliaform interneurons into cortical circuits. Nat Neurosci 18:393-401
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

Showing the most recent 10 out of 23 publications