tetrodotoxin and Hypothyroidism

Thyroid hormone deficiency during a critical period of development severely affects cognitive functions, resulting in profound mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the development of the intrinsic properties of CA1 hippocampal pyramidal cells. These cells are known to exhibit different firing patterns during development, being classified as either regular-spiking or burst-spiking cells. Patch-clamp experiments showed that hypothyroid rats presented a larger number of regular-spiking cells at early postnatal age (P9-11). This difference in firing-pattern distribution disappeared at the pre-weanling age (P17-19), when almost every cell displayed bursting behavior in both control and hypothyroid rats. However, when studied in detail, weanling hypothyroid rats presented a smaller number of spikes per burst than did control animals. One of the major factors behind bursting behavior is sustained depolarization following an action potential. In this study, we show that action potential afterdepolarizations of hypothyroid animals registered shorter half-durations than did controls, a fact which could explain the smaller number of action potentials per burst. Additionally, the afterdepolarizations observed on both hypothyroid and control neurons were highly sensitive to low concentrations of nickel, suggesting that a low-threshold Ca(2+) current is key in the generation of spike afterdepolarizations and in the control of the bursting pattern of firing of these neurons. In agreement with this, experiments performed on dissociated hippocampal neurons have shown that this current is significantly depressed in hypothyroid animals. Therefore, we conclude that an alteration of the low-threshold calcium current is the basic factor explaining the differences observed in the firing behavior of hypothyroid animals.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Age Factors; Animals; Animals, Newborn; Biophysics; Calcium; Calcium Channels; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; Hippocampus; Hypothyroidism; In Vitro Techniques; Methimazole; Neurons; Patch-Clamp Techniques; Picrotoxin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin

To examine the effect of thyroid status on the homeostatic control of intracellular Na+, we studied the effect of treatment of hypothyroid rabbits with 3,5,3'-triiodothyronine (T3). Intracellular Na+ and pH (pHi) in papillary muscles and Na+-K+ pump current (Ip) in ventricular myocytes were measured with ion-sensitive microelectrode and whole cell patch-clamp techniques. Na+ influx, estimated from the rate of increase in intracellular Na+ on sudden Na+-K+ pump blockade with dihydroouabain, and Na+ efflux, calculated from Ip, were similar. Treatment with T3 induced an increase in both Na+ influx and Ip. The treatment-induced increase in Na+ influx was eliminated by 5-(N,N-dimethyl)amiloride (DMA) but not by tetrodotoxin. Treatment with T3 increased the rate of fall in pHi on exposure of the papillary muscles to DMA; when the buffer capacity was taken into account, the T3 treatment-induced increase in this rate corresponded well with the treatment-induced, DMA-inhibitable estimate of Na+ uptake. We conclude that thyroid hormone enhances both Na+-H+ exchange-mediated Na+ uptake and Na+-K+ pump-mediated Na+ efflux.

Topics: Amiloride; Animals; Cells, Cultured; Heart; Heart Ventricles; Homeostasis; Hydrogen-Ion Concentration; Hypothyroidism; In Vitro Techniques; Kinetics; Male; Membrane Potentials; Myocardium; Ouabain; Papillary Muscles; Propylthiouracil; Rabbits; Sodium; Sodium-Potassium-Exchanging ATPase; Tetrodotoxin; Thyroid Gland; Triiodothyronine