The past few years marks a renaissance in the study of electrical synapses which have been shown to exist in an ever-increasing number of areas across the mammalian brain. Despite the overwhelming evidence for their importance and widespread distribution, still little is known about their ability to undergo plastic changes. The notion that mammalian electrical synapses could be as dynamic and modifiable as chemical synapses could dramatically change our perception about their properties and functional relevance. Electrical synapses at identifiable mixed synaptic contacts on goldfish Mauthner cells are regulated by their co-localized glutamatergic synapses, whose activity induces long-term potentiation of electrical transmission via NMDA receptor activation. Recent data show that electrical transmission at these terminals is mediated by connexin35, the fish ortholog of the mammalian neuronal connexin36. The widespread distribution of connexin36 and the ubiquity of the proposed regulatory elements suggest that mammalian electrical synapses may be similarly regulated. We propose to test this prediction at electrical synapses in the rat, in particular at those of the Inferior Olive, where ultrastructural and physiological features appear to favor such possibility.
Aim 1 tests the hypothesis that electrical synapses between inferior olivary cells are regulated by the activity of neighboring glutamatergic synapses. It is based on preliminary ultrastructural studies suggesting that, as in goldfish mixed synapses, gap junctions labeled for connexin36 are in close proximity to postsynaptic densities labeled for NMDA receptors, sufficiently close for diffusion of signaling molecules between the two types of structures.
Aim 2 is to investigate the mechanisms underlying activity-dependent changes in electrical transmission. We will ask if the mechanistic requirements are similar to those found for Mauthner cell synapses (involving NMDA receptor activation of CaM-KII) or, alternatively, different signaling pathways are involved. The proposed research addresses the novel concept that the strength of mammalian electrical synapses is dynamically modified by the activity of nearby chemical synapses. This property could be widespread and relevant to pathological conditions such as epilepsy and developmental disorders. The application explores the possibility that chemically mediated synapses, the main form of interneuronal communication in the mammalian brain, regulate the function of gap junction-mediated electrical synapses. Because electrical synapses have been shown to promote coordinated neuronal activity, the existence of such regulation could have profound physiological and pathological implications, contributing to epilepsy and to cognitive (psychiatric) and developmental disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS055726-02
Application #
7469564
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Talley, Edmund M
Project Start
2007-07-15
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$181,563
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
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
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
Miller, Adam C; Pereda, Alberto E (2017) The electrical synapse: Molecular complexities at the gap and beyond. Dev Neurobiol 77:562-574
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 :
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
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
Pereda, Alberto E (2014) Electrical synapses and their functional interactions with chemical synapses. Nat Rev Neurosci 15:250-63
Pereda, Alberto E; Schweizer, Felix E; Zottoli, Steven J (2013) On the training of future neuroscientists: insights from the Grass laboratory. Neuron 79:12-5
Palacios-Prado, Nicolás; Hoge, Gregory; Marandykina, Alina et al. (2013) Intracellular magnesium-dependent modulation of gap junction channels formed by neuronal connexin36. J Neurosci 33:4741-53
Rash, John E; Curti, Sebastian; Vanderpool, Kimberly G et al. (2013) Molecular and functional asymmetry at a vertebrate electrical synapse. Neuron 79:957-69

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