Gap junction (GJ)-mediated electrical synapses were recently reported to underlie important network properties in the dorsal cochlear nucleus and anatomical evidence suggests they are widespread along the auditory pathway. However, the properties of auditory electrical synapses remain poorly understood. As their chemical counterparts, electrical synapses are ?plastic?, that is, they modify their strength with activity. Changes in the strength of electrical synapses dynamically reconfigure neuronal circuits in various neural structures. Thus, the presence and plastic properties of electrical synapses could fundamentally change the way we understand the organization of auditory circuits and, ultimately, the processing of auditory information. This proposal aims to contribute to our understanding of electrical transmission in the auditory system by investigating the molecular mechanisms causing plastic changes in GJ communication at mixed, electrical and chemical, contacts that couple primary auditory afferents to the Mauthner (M-) cells in fish. Our work in goldfish shows that electrical (and chemical) transmission at these mixed synapses undergo activity-dependent potentiation. Because these dynamic properties were later found to occur at mammalian electrical synapses. M-cell mixed synapses are considered a valuable model to study plasticity of vertebrate electrical transmission. In contrast to chemical synapses, little is known about the molecular mechanisms that underlie changes in the strength of electrical synapses. It is currently thought that plastic changes in GJ conductance are due to direct modification of the properties of already existing channels. However, our progress suggests that regulated insertion and removal of GJ channels may also contribute to plasticity. We propose to investigate the contribution of regulated trafficking of GJ channels to plastic changes of electrical transmission and its molecular underpinnings. To directly examine this possibility, we will take these unique model mixed synapses to a new level of analysis by investigating their properties in larval zebrafish. The amenability of zebrafish larvae to image the movement of fluorescently-tagged GJ channels in-vivo should allow monitoring of active synapses undergoing plasticity. This approach will provide an unprecedented window for the analysis of electrical transmission at which detailed molecular mechanisms will be investigated by combining in-vivo imaging, electrophysiology and time-resolved ultrastructural analysis with powerful genetic manipulations.
Aim 1 is to investigate the conditions under which electrical synapses in larval zebrafish undergo potentiation. By combining electrophysiology and pharmacology with electrical and optogenetic stimulation, this aim will identify the conditions under which larval mixed synapses undergo potentiation of electrical (and chemical) transmission.
Aim 2 is to test whether insertion and removal of GJ channels are required for plastic changes.
This aim will explore the notion that electrical synapses are complex synaptic structures at which channels turnover and that their proper function and regulation results from interactions between multiple proteins. The description of novel molecular mechanisms involved in their regulation will contribute to a better understanding of the dynamics of circuits relevant to auditory dysfunction and the potential identification of novel therapeutic targets.

Public Health Relevance

Gap junction mediated electrical synapses were recently reported to underlie important network properties in the dorsal cochlear nucleus and anatomical evidence suggests they are widespread along the auditory pathway. However, the properties of auditory electrical synapses remain poorly understood. As their chemical counterparts, electrical synapses are ?plastic?, that is, they modify their strength with activity. Changes in the strength of electrical synapses dynamically reconfigure neuronal circuits in various neural structures. Thus, the presence and plastic properties of electrical synapses could fundamentally change the way we understand the organization of auditory circuits and, ultimately, the processing of auditory information. This proposal aims to contribute to our understanding of electrical transmission in the auditory system by investigating the molecular mechanisms causing plastic changes in gap junction communication at mixed, electrical and chemical, contacts that couple primary auditory afferents to the Mauthner cells in fish, which are considered a valuable model for investigating plasticity of vertebrate electrical transmission. Our progress in goldfish shows that electrical (and chemical) transmission at these mixed synapses undergoes activity-dependent potentiation. We propose to investigate the contribution of trafficking of gap junction channels as a possible mechanism for regulating the strength of electrical transmission. To directly examine this possibility, we will take these unique model mixed synapses to a new level of analysis by investigating their properties in larval zebrafish. The amenability of zebrafish larvae for experimentation will provide an unprecedented window for the analysis of electrical transmission at which detailed molecular mechanisms will be investigated by combining in-vivo imaging, electrophysiology and time-resolved ultrastructural analysis with powerful genetic manipulations. The proposed research will expose novel mechanisms of regulation of auditory electrical synapses that will contribute to a deeper understanding of circuits relevant to auditory dysfunction and the potential identification of novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC011099-12
Application #
10086461
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2010-07-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
12
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
Faber, Donald S; Pereda, Alberto E (2018) Two Forms of Electrical Transmission Between Neurons. Front Mol Neurosci 11:427
Jain, Roshan A; Wolman, Marc A; Marsden, Kurt C et al. (2018) A Forward Genetic Screen in Zebrafish Identifies the G-Protein-Coupled Receptor CaSR as a Modulator of Sensorimotor Decision Making. Curr Biol 28:1357-1369.e5
Nagy, James I; Pereda, Alberto E; Rash, John E (2018) Electrical synapses in mammalian CNS: Past eras, present focus and future directions. Biochim Biophys Acta Biomembr 1860:102-123
Nagy, James I; Pereda, Alberto E; Rash, John E (2017) On the occurrence and enigmatic functions of mixed (chemical plus electrical) synapses in the mammalian CNS. Neurosci Lett :
Miller, Adam C; Pereda, Alberto E (2017) The electrical synapse: Molecular complexities at the gap and beyond. Dev Neurobiol 77:562-574
Pereda, Alberto E; Macagno, Eduardo (2017) Electrical transmission: Two structures, same functions? Dev Neurobiol 77:517-521
Haas, Julie S; Greenwald, Corey M; Pereda, Alberto E (2016) Activity-dependent plasticity of electrical synapses: increasing evidence for its presence and functional roles in the mammalian brain. BMC Cell Biol 17 Suppl 1:14
Rash, J E; Kamasawa, N; Vanderpool, K G et al. (2015) Heterotypic gap junctions at glutamatergic mixed synapses are abundant in goldfish brain. Neuroscience 285:166-93
Cachope, Roger; Pereda, Alberto E (2015) Opioids potentiate electrical transmission at mixed synapses on the Mauthner cell. J Neurophysiol 114:689-97
Yao, Cong; Vanderpool, Kimberly G; Delfiner, Matthew et al. (2014) Electrical synaptic transmission in developing zebrafish: properties and molecular composition of gap junctions at a central auditory synapse. J Neurophysiol 112:2102-13

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