The long-term objective of the proposed research is to study the modulatory actions of endocannabinoids on synaptic transmission in the CNS. The experimental model involves identified mixed electrical and chemical (glutamatergic) synapses between eighth nerve auditory primary afferents and the goldfish Mauthner (M-) cell and neighboring (GABA/Glycine) inhibitory terminals. While most studies describing the role of endocannabinoids on synaptic transmission have utilized in-vitro systems, this preparation uniquely allows continuous monitoring and quantification of changes in electrical and chemical transmission in-vivo. So far, endocannabinoids have been reported to depress chemical synaptic transmission via presynaptic activation of cannabinoid type 1 receptors (CB1Rs). Contrasting this notion, our preliminary results show that activation of CB1Rs enhances synaptic transmission at these inputs on the M-cell. Intradendritic recordings, molecular biology techniques, and immunocytochemistry, will be used to test specific hypotheses and mechanisms underlying modifications of synaptic transmission induced by this agonist.
Aim 1, explores the action of different cannabinoid agonists and endocannabinoids on the synaptic efficacy of mixed synapses and inhibitory terminals. It is based on data suggesting that activation of CB1R leads to long-lasting enhancement of both electrical and chemical transmission at mixed synapses. These changes also included nearby inhibitory terminals. I will explore the actions of locally applied cannabinoid agonists and endocannabinoids on unitary and population synaptic responses and membrane conductances that are relevant for the function of this auditory input.
Aim 2 is to investigate the mechanisms underlying these long-term changes in synaptic transmission. It is based on the finding that dopamine receptor antagonists block the potentiation triggered by CB1R activation. We have previously reported the presence of a dopaminergic innervation and application of dopamine evoked lasting enhancements of the synaptic response. We will test the hypothesis that cannabinoid-evoked potentiation is mediated via dopamine release from neighboring varicosities. We will also ask under which physiological conditions and from which particular cell type endocannabinoids are released. The proposed research addresses the concept that modulation of intercellular communication by endocannabinoids is not restricted to chemical synapses but also include gap-junction mediated electrical synapses. Moreover, based on a functional interaction with the dopaminergic system, it can lead to long-term potentiation of synaptic responses. This modulatory action could constitute a widespread property, relevant not only to normal brain function in structures such as the basal ganglia, retina, and neocortex where both forms of transmission co-exist, but also to numerous health-related issues such as drug abuse. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS052827-01A1
Application #
7105996
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Talley, Edmund M
Project Start
2006-03-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$289,335
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
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
Pereda, Alberto E; Macagno, Eduardo (2017) Electrical transmission: Two structures, same functions? Dev Neurobiol 77:517-521
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 :
Pereda, Alberto E (2014) Electrical synapses and their functional interactions with chemical synapses. Nat Rev Neurosci 15:250-63
Pereda, Alberto E; Curti, Sebastian; Hoge, Gregory et al. (2013) Gap junction-mediated electrical transmission: regulatory mechanisms and plasticity. Biochim Biophys Acta 1828:134-46
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
Rash, John E; Curti, Sebastian; Vanderpool, Kimberly G et al. (2013) Molecular and functional asymmetry at a vertebrate electrical synapse. Neuron 79:957-69
Cachope, Roger; Pereda, Alberto E (2012) Two independent forms of activity-dependent potentiation regulate electrical transmission at mixed synapses on the Mauthner cell. Brain Res 1487:173-82
Curti, Sebastian; Hoge, Gregory; Nagy, James I et al. (2012) Synergy between electrical coupling and membrane properties promotes strong synchronization of neurons of the mesencephalic trigeminal nucleus. J Neurosci 32:4341-59

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