This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of the neurophysiological mechanisms responsible for modulating the activity of synaptic inputs to hilar mossy cells. These unusual excitatory local circuit neurons receive strong glutamatergic, GABAergic, and likely cholinergic innervation from a variety of intrinsic and extrinsic sources. Normal function of mossy cells has been postulated to play a prominent role in information processing and memory formation in the hippocampus, while their loss and/or dysfunction has been implicated in the etiology of temporal lobe epilepsy. Preliminary data indicate that the activity of both inhibitory and excitatory inputs to mossy cells is modulated by depolarization-induced release of endogenous cannabinoids.
Aim 1 of this proposal will provide a complete characterization of cannabinoid dependent signaling initiated by activation of mossy cells, and examine the role of postsynaptic cholinergic receptors in modulating the threshold for endocannabinoid release. Preliminary data has also indicated that presynaptic GABAergic receptors are expressed on some excitatory afferents to hilar mossy cells and further suggested that these receptors are likely subject to tonic inhibition by ambient GABA. Thus, Aim 2 will focus on ambient GABA as a potential modulator of these excitatory afferents and will ultimately determine if there is a useful relationship between endocannabinoid mediated retrograde signaling and inhibitory tone. Finally, Aim 3 will test the hypothesis that endocannabinoid mediated retrograde signaling in this system is impaired by chronic exposure to natural and/or synthetic cannabinoid agonists. These experiments may expose specific neurophysiological mechanisms that are fundamentally involved in regulation of excitability, information processing, and memory formation in the dentate gyrus, and further determine how they are altered over time in a chronic model of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019576-02
Application #
7093652
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lin, Yu
Project Start
2005-07-15
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$280,607
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Hofmann, Mackenzie E; Bhatia, Chinki; Frazier, Charles J (2011) Cannabinoid receptor agonists potentiate action potential-independent release of GABA in the dentate gyrus through a CB1 receptor-independent mechanism. J Physiol 589:3801-21
Hofmann, Mackenzie E; Frazier, Charles J (2010) Muscarinic receptor activation modulates the excitability of hilar mossy cells through the induction of an afterdepolarization. Brain Res 1318:42-51
Lindsly, Casie; Frazier, Charles J (2010) Two distinct and activity-dependent mechanisms contribute to autoreceptor-mediated inhibition of GABAergic afferents to hilar mossy cells. J Physiol 588:2801-22
Nahir, Ben; Lindsly, Casie; Frazier, Charles J (2010) mGluR-mediated and endocannabinoid-dependent long-term depression in the hilar region of the rat dentate gyrus. Neuropharmacology 58:712-21
Hofmann, Mackenzie E; Nahir, Ben; Frazier, Charles J (2008) Excitatory afferents to CA3 pyramidal cells display differential sensitivity to CB1 dependent inhibition of synaptic transmission. Neuropharmacology 55:1140-6
Frazier, Charles J (2007) Endocannabinoids in the dentate gyrus. Prog Brain Res 163:319-37
Nahir, Ben; Bhatia, Chinki; Frazier, Charles J (2007) Presynaptic inhibition of excitatory afferents to hilar mossy cells. J Neurophysiol 97:4036-47
Hofmann, Mackenzie E; Nahir, Ben; Frazier, Charles J (2006) Endocannabinoid-mediated depolarization-induced suppression of inhibition in hilar mossy cells of the rat dentate gyrus. J Neurophysiol 96:2501-12