title: Evidence for homeostatic adjustments of rat somatosensory cortical neurons to changes in extracellular acetylcholine concentrations produced by iontophoretic administration of acetylcholine and by systemic diisopropylfluorophosphate treatment.
abstract: We describe the responses of single units in the awake (24 cells) or urethane-anesthetized (37 cells) rat somatosensory cortex during repeated iontophoretic pulses (1.0 s, 85 nA) of acetylcholine, both before and after systemic treatment with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (i.p., 0.3-0.5 LD50). The time-course of the response to acetylcholine pulses differed among cortical neurons but was characteristic for a given cell. Different time-courses included monophasic excitatory or inhibitory responses, biphasic (excitatory-inhibitory, inhibitory-excitatory, excitatory-excitatory, and inhibitory-inhibitory), and triphasic (excitatory-excitatory-inhibitory, inhibitory-inhibitory-excitatory, and inhibitory-excitatory-inhibitory) responses. Although the sign and time-course of the individual responses remained consistent, their magnitude fluctuated across time; most cells exhibited either an initial increase or decrease in response magnitude followed by oscillations in magnitude that diminished with time, gradually approaching the original size. The time-course of the characteristic response to an acetylcholine pulse appeared to determine direction and rate of change in response magnitude with successive pulses of acetylcholine. Diisopropylfluorophosphate treatment, given 1 h after beginning repeated acetylcholine pulses, often resulted in a gradual increase in spontaneous activity to a slightly higher but stable level. Superimposed on this change in background activity, the oscillations in the response amplitude reappeared and then subsided in a pattern similar to the decay seen prior to diisopropylfluorophosphate treatment. Our results suggest that dynamic, homeostatic mechanisms control neuronal excitability by adjusting the balance between excitatory and inhibitory influences within the cortical circuitry and that these mechanisms are engaged by prolonged increases in extracellular acetylcholine levels caused by repeated pulses of acetylcholine and by acetylcholinesterase inhibition. However, this ability of neurons in the cortical neuronal network to rapidly adjust to changes in extracellular levels of acetylcholine questions the potential efficacy of therapeutic treatments designed to increase ambient levels of acetylcholine as a treatment for Alzheimer's disease or to enhance mechanisms of learning and memory.
authors.affiliation: Unité de biophysique, Centre de recherches du service de Santé des Armées, Grenoble, France.
authors.forename: G
authors.initials: G
authors.lastname: Testylier
authors.forename: M
authors.initials: M
authors.lastname: Maalouf
authors.forename: A E
authors.initials: AE
authors.lastname: Butt
authors.forename: A A
authors.initials: AA
authors.lastname: Miasnikov
authors.forename: R W
authors.initials: RW
authors.lastname: Dykes
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004569:Electroencephalography; D004576:Electromyography; D005110:Extracellular Space / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007267:Injections; D007478:Iontophoresis; D007531:Isoflurophate / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000502:physiology; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013003:Somatosensory Cortex / Q000166:cytology / Q000502:physiology*; D014520:Urethane
chemical_list: D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D014520:Urethane; D000109:Acetylcholine