Acetylcholine acting through muscarinic receptors modulates the excitability of neurons by altering various sodium, calcium, and potassium channels. This modulation of excitability plays a central role in cholinergic regulation of wakefulness, cognition, and memory. The goal of the proposed research is to understand muscarinic changes in action potential formation and firing patterns in terms of modulation of particular ion channels. Patch clamp techniques will be used to study the control of sodium, potassium, calcium channels in sympathetic, hippocampal, and dopamine neurons by muscarinic stimulation. The primary experimental preparation will be acutely isolated neurons, which allow voltage-clamp with sufficient speed to characterize modulation of the large, rapid currents flowing during action potentials. This will extend previous work using brain slices, in which only relatively small and slow currents could be studied under voltage-clamp. We will directly examine currents flowing during action potentials by first recording action potential wave-forms and, in the same cell, using those wave forms as command voltages in voltage clamp experiments. By using pharmacological tools to separate individual current sand performing both current-clamp and voltage-clamp experiments in the presence of acetylcholine, it should be possible to determine the role of modulation of particular channel types in contribution to overall changes in excitability. Muscarinic control of ion channels and neuronal excitability is a basic process for the normal operation of the brain, and evidence suggests changes in the aging brain. Changes in muscarinic modulation of hippocampal neurons may be centrally involved in the symptoms of Alzheimer's disease, and better understanding of the channels involved may lead to novel therapeutic interventions, for example by using ion channel blockers to mimic effects of acetylcholine.

Project Start
1998-12-01
Project End
1999-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Richards, Kathryn S; Swensen, Andrew M; Lipscombe, Diane et al. (2007) Novel CaV2.1 clone replicates many properties of Purkinje cell CaV2.1 current. Eur J Neurosci 26:2950-61
McDonough, Stefan I; Mori, Yasuo; Bean, Bruce P (2005) FPL 64176 modification of Ca(V)1.2 L-type calcium channels: dissociation of effects on ionic current and gating current. Biophys J 88:211-23
Blitz, Dawn M; Regehr, Wade G (2003) Retinogeniculate synaptic properties controlling spike number and timing in relay neurons. J Neurophysiol 90:2438-50
Blair, Nathaniel T; Bean, Bruce P (2003) Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons. J Neurosci 23:10338-50
Do, Michael Tri H; Bean, Bruce P (2003) Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation. Neuron 39:109-20
Martina, Marco; Yao, Gui Lan; Bean, Bruce P (2003) Properties and functional role of voltage-dependent potassium channels in dendrites of rat cerebellar Purkinje neurons. J Neurosci 23:5698-707
Swensen, Andrew M; Bean, Bruce P (2003) Ionic mechanisms of burst firing in dissociated Purkinje neurons. J Neurosci 23:9650-63
Mitterdorfer, Jorg; Bean, Bruce P (2002) Potassium currents during the action potential of hippocampal CA3 neurons. J Neurosci 22:10106-15
Blair, Nathaniel T; Bean, Bruce P (2002) Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci 22:10277-90
Chen, Chinfei; Blitz, Dawn M; Regehr, Wade G (2002) Contributions of receptor desensitization and saturation to plasticity at the retinogeniculate synapse. Neuron 33:779-88

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