Synaptic physiology in the hippocampus is characterized by strong local inhibitory circuits that the influence of excitatory synaptic transmission. The neurotransmitter norepinephrine (NE), regulates synaptic inhibition in the hippocampus in two important ways. Acting at alpha adrenoceptors, NE produces disinhibition, a reduction in stimulus- evoked inhibitory postsynaptic potentials, through an unknown action on inhibitory interneurons. It also increases tonic synaptic inhibition by directly stimulating action potential discharge in interneurons. Both of these actions may participate in the well-known, but poorly understood, action of NE to reduce epileptic activity eg 54,55. Here we propose a thorough examination of the disinhibitory action of NE, to define its underlying physiological mechanisms. The proposed studies will concentrate on the actions of NE on hippocampal interneurons; Previously, we have identified three mechanisms that may underlie adrenergic disinhibition; Blockade of excitatory synaptic activation of oriens/alveus interneurons, direct depolarization of these interneurons, leading to loss of responsiveness, and, hyperpolarization of lacunosum- molecular interneurons, leading to a loss of distal slow inhibition in area CA1 of the hippocampus. Experiments will be directed at determining a mechanism for these effects and understanding their role in controlling hippocampal excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH056454-05
Application #
6392193
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Program Officer
Asanuma, Chiiko
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$162,942
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Mitra, Ananya; Blank, Martina; Madison, Daniel V (2012) Developmentally altered inhibition in Ts65Dn, a mouse model of Down syndrome. Brain Res 1440:1-8
Hanson, Jesse E; Blank, Martina; Valenzuela, Ricardo A et al. (2007) The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome. J Physiol 579:53-67
Montgomery, Johanna M; Selcher, Joel C; Hanson, Jesse E et al. (2005) Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state. BMC Neurosci 6:48
Montgomery, Johanna M; Madison, Daniel V (2002) State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33:765-77
McQuiston, A R; Madison, D V (1999) Muscarinic receptor activity has multiple effects on the resting membrane potentials of CA1 hippocampal interneurons. J Neurosci 19:5693-702
McQuiston, A R; Madison, D V (1999) Muscarinic receptor activity induces an afterdepolarization in a subpopulation of hippocampal CA1 interneurons. J Neurosci 19:5703-10
McQuiston, A R; Madison, D V (1999) Nicotinic receptor activation excites distinct subtypes of interneurons in the rat hippocampus. J Neurosci 19:2887-96