Abstract

The objective is to elucidate mechanisms of long-term potentiation (LPT) and norepinephrine-induced long-lasting potentiation (NELLP) in the dentate gyrus of the hippocampal formation. Electrophysiological methods will be employed to record evoked potentials and membrane biophysical properties of neurons in the dentate gyrus of the in vitro rat hippocampal slice preparation. LTP will be evoked by a burst of high frequency, repetitive electrical stimulation to the monosynaptic perforant path input. NELLP will be induced by bath application of norepinephrine (NE). Previous experiments have demonstrated that (1) LTP and LLP in the dentate require activation of Beta-adrenergic receptors by NE; (2) adenylate cyclase, linked to Betarecptors increases cAMP levels; (3) inhibitors of protein synthesis can prevent the development of LTP and NELLP; and (4) a monoclonal antibody against a hippocampal cell surface antigen can prevent LTP. It is hypothesized that NE, released by high frequency electrical stimulation (LTP) or exogenously applied (NELLP), enhances synthesis of cAMP. Cyclic AMP increases phosphorylation of proteins which may initiate protein synthesis and modify activity of enzymes and structural proteins. A cell surface protein, possibly one of those whose synthesis or phosphorylation is regulated by NE, or possibly a molecule which regulates the action of NE, is intimately involved in LTP. This hypothesis will be tested by (1) comparing the electrophysiological effects of high frequency stimulation and NE and of Beta-adrenergic antagonists on LTP and NELLP, (2) comparing cAMP production and phosphorylation of specific protein fractions after repetitive stimulation or exposure to NE, in the presence and absence of Beta-antagonists, (3) determining the effect of inhibitors of mRNA synthesis or protein synthesis on production and maintenance of LTP, NELLP, and forskolin-induced LLP, and (4) determining the physiological effects and site of action of a monoclonal antibody that blocks LTP.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023865-02
Application #
3407836
Study Section
Neurology A Study Section (NEUA)
Project Start
1987-04-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20852

  Publications

Lea 4th, Paul M; Sarvey, John M (2003) Modulation of epileptiform burst frequency by the metabotropic glutamate receptor subtype mGluR3. Epilepsy Res 53:207-15
Li, Y; Hough, C J; Frederickson, C J et al. (2001) Induction of mossy fiber --> Ca3 long-term potentiation requires translocation of synaptically released Zn2+. J Neurosci 21:8015-25
Lea 4th, P M; Wroblewska, B; Sarvey, J M et al. (2001) beta-NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor. J Neurophysiol 85:1097-106
Li, Y; Hough, C J; Suh, S W et al. (2001) Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol 86:2597-604
Bramham, C R; Southard, T; Ahlers, S T et al. (1998) Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats. Brain Res 789:245-55
Bramham, C R; Bacher-Svendsen, K; Sarvey, J M (1997) LTP in the lateral perforant path is beta-adrenergic receptor-dependent. Neuroreport 8:719-24
Bramham, C R; Southard, T; Sarvey, J M et al. (1996) Unilateral LTP triggers bilateral increases in hippocampal neurotrophin and trk receptor mRNA expression in behaving rats: evidence for interhemispheric communication. J Comp Neurol 368:371-82
Bramham, C R; Sarvey, J M (1996) Endogenous activation of mu and delta-1 opioid receptors is required for long-term potentiation induction in the lateral perforant path: dependence on GABAergic inhibition. J Neurosci 16:8123-31
Burgard, E C; Cote, T E; Sarvey, J M (1993) Muscarinic depression of synaptic transmission and blockade of norepinephrine-induced long-lasting potentiation in the dentate gyrus. Neuroscience 54:377-89
Burgard, E C; Sarvey, J M (1991) Long-lasting potentiation and epileptiform activity produced by GABAB receptor activation in the dentate gyrus of rat hippocampal slice. J Neurosci 11:1198-209

Showing the most recent 10 out of 16 publications