This project will investigate the functions of electrical synapses within inhibitory circuits of the mammalian forebrain. "Electrical synapses" are gap junctions that interconnect neurons, and they serve as rapid, bidirectional communication pathways. A considerable amount is known about the basic biophysical properties of mammalian electrical synapses, their locations, and their dependence on the gap junction protein connexin36 (Cx36). Gap junctions can strongly influence the timing, phase, synchrony, probability, and rate of action potentials in pairs and small groups of neurons, yet we still do not know how electrical synapses contribute to larger network functions. The complexity of forebrain circuits has long been an impediment, but powerful new genetic and optical tools can now be brought to bear on these issues. Remarkably, in the mature thalamus and neocortex electrical synapses occur almost exclusively between GABAergic neurons. These junctions are quite specific;they usually interconnect inhibitory neurons of the same subtype in the cortex, and excitatory cells in the mature forebrain rarely express them. This investigation will focus on the roles of electrical synapses that interconnect inhibitory neurons of the thalamus (specifically in the somatosensory thalamic reticular nucleus, TRN), and several subtypes of interneurons in the neocortex (barrel cortex). There are three specific aims. The first is to determine the roles of electrical synapses in thalamocortical network activity, specifically slow (delta, theta) and fast (gamma) network oscillations studied in vitro and in vivo. We will use electrophysiology, selective deletion of Cx36 from subtypes of cortical and thalamic inhibitory cells, and optogenetics to control specific neurons and axonal pathways.
The second aim i s to test the hypothesis that electrical synapses play an important role in the powerful feedforward inhibitory circuits activated by both thalamocortical and corticothalamic pathways.
The third aim i s to define the spatial and cell type-specific organization of gap junction-coupled networks in somatosensory segments of the TRN and neocortex. Inhibitory circuits are universal, and essential for all sensory, motor, and cognitive functions;electrical synapses are ubiquitous components of inhibitory circuits. Abnormalities of inhibition are implicated in a wide variety of neurological, psychiatric, and developmental disorders, and mutations in gap junction genes are associated with epilepsy and other neurological dysfunctions. Our investigation will help to clarify the relevance and functions of electrical synapses in inhibitory systems of the forebrain.

Public Health Relevance

Many nerve cells in the brain communicate with one another via specialized structures called electrical synapses. Mutations of genes critical for electrical synapses can cause epilepsy and other neurological disorders that involve abnormal types of neural rhythms and synchrony. This project will test the hypothesis that electrical synapses between inhibitory cells of the forebrain are important for generating and controlling brain rhythms and dynamics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS050434-06
Application #
8704482
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Talley, Edmund M
Project Start
2005-01-15
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$483,438
Indirect Cost
$159,688
Name
Brown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Lee, Seung-Chan; Patrick, Saundra L; Richardson, Kristen A et al. (2014) Two functionally distinct networks of gap junction-coupled inhibitory neurons in the thalamic reticular nucleus. J Neurosci 34:13170-82
Fanselow, Erika E; Connors, Barry W (2010) The roles of somatostatin-expressing (GIN) and fast-spiking inhibitory interneurons in UP-DOWN states of mouse neocortex. J Neurophysiol 104:596-606
Connors, Barry W; Zolnik, Timothy A; Lee, Seung-Chan (2010) Enhanced Functions of Electrical Junctions. Neuron 67:354-356
Lee, Seung-Chan; Cruikshank, Scott J; Connors, Barry W (2010) Electrical and chemical synapses between relay neurons in developing thalamus. J Physiol 588:2403-15
Cruikshank, Scott J; Urabe, Hayato; Nurmikko, Arto V et al. (2010) Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons. Neuron 65:230-45
Parker, Philip R L; Cruikshank, Scott J; Connors, Barry W (2009) Stability of electrical coupling despite massive developmental changes of intrinsic neuronal physiology. J Neurosci 29:9761-70
Fanselow, Erika E; Richardson, Kristen A; Connors, Barry W (2008) Selective, state-dependent activation of somatostatin-expressing inhibitory interneurons in mouse neocortex. J Neurophysiol 100:2640-52
Mancilla, Jaime G; Lewis, Timothy J; Pinto, David J et al. (2007) Synchronization of electrically coupled pairs of inhibitory interneurons in neocortex. J Neurosci 27:2058-73
Landisman, Carole E; Connors, Barry W (2005) Long-term modulation of electrical synapses in the mammalian thalamus. Science 310:1809-13