The effects of intrauterine growth retardation on the development of the Purkinje cell dendritic tree in the cerebellar cortex of fetal sheep: a note on the ontogeny of the Purkinje cell.

The development of the fetal sheep cerebellum at 80, 100, 120 and 140 days gestation (term = 146 days) and 3 months postnatally was studied using Nissl stained sections and rapid Golgi preparations. The most rapid expansion of the Purkinje cell dendritic tree occurred between 100 and 120 days of gestation (5-6 fold increase in area). By 140 days it had acquired its adult form after which time growth continued mainly in the vertical direction. The effects of intrauterine growth retardation on the growth of granule and Purkinje cell dendrites in the cerebellar cortex of fetal sheep (140 days) were investigated in Golgi preparations. Compared with control cerebella the length (but not the number) of granule cell dendrites was reduced by 14% (P less than 0.01); the area of the Purkinje cell dendritic field was reduced by 20% (P less than 0.01); the branching density was reduced by 8% (P less than 0.01); the total branch length was reduced by 27% (P less than 0.002); the density of dendritic spines per row was not affected. These factors resulted in a decrease of 26% (P less than 0.002) in the total number of dendritic spines per row per Purkinje cell. These findings show that the growth of granule cell dendrites and the Purkinje cell dendritic tree have been significantly affected by chronic intrauterine deprivation. Such structural abnormalities could affect the pattern of neuronal connectivity and could be associated with functional deficits.

Intracellular K+ activity, intracellular Na+ activity and maximum diastolic potential of canine subendocardial Purkinje cells from one-day-old infarcts.

The basis for the reduced maximum diastolic potential of canine cardiac subendocardial Purkinje fibers surviving one day after extensive transmural infarction was investigated, using double-barrel potassium and sodium ion-sensitive microelectrodes. The maximum diastolic potential of Purkinje fibers in infarct preparations from the left ventricular apex measured during the first hour of superfusion in a tissue bath was -50.1 +/- 13.7 mV, a value markedly reduced from the value in control Purkinje fibers from noninfarcted preparations (-85.0 +/- 4.5 mV). The intracellular potassium ion activity was reduced by 50.4 mM during this time (intracellular potassium ion activity equals 61.6 +/- 16.1 mM, as compared to control intracellular potassium ion activity of 112 +/- 19.8 mM). The potassium equilibrium potential was reduced by 16.0 mV (from -97.2 +/- 4.7 mV in controls to -81.2 +/- 6.9 mV), thus accounting for about one half of the reduction in the maximum diastolic potential. After 6 hours of superfusion, the maximum diastolic potential increased to -78.9 +/- 8.7 mV (still significantly less than control). The potassium equilibrium potential had largely recovered (-93.8 +/- 5.9 mV). The intracellular sodium ion activity of Purkinje fibers in the infarcts (15.6 +/- 6.9 mM) was elevated during the first hour of superfusion by 6.2 mM compared to control (9.4 +/- 2.6 mM), and this was only 12% as much as the initial intracellular potassium ion activity decrease. Sodium ion activity after 3-6 hours of superfusion was not significantly different than normal (12.1 +/- 4.9 mM). In conclusion, only a portion of the maximum diastolic potential changes can be explained by a reduction of the potassium equilibrium potential. It is likely that change(s) in the cell membrane sodium-potassium pump's function and in the membrane conductance are also involved. Furthermore, the lack of a compensatory increase in intracellular sodium ion activity accompanying the large reduction of intracellular potassium ion activity may be a consequence of the cellular acidosis, which is known to occur during myocardial ischemia.

Intrinsic neuronal electroresponsiveness and its possible role in epileptogenesis.

An increased neuronal excitability is one of the most important factors involved in the physiopathology of epileptic states. It may occur via two major routes: an increase in cation inflow, a decreasing cation outflow. The recent discovery that Na+ and Ca2+ inflow may occur through channels that do not inactivate (close) rapidly and that can therefore produce plateau action potentials of great duration, make these conductances quite significant in the generation and maintenance of epilepsy. The presence of excitatory neurotransmitters released either by presynaptic terminal or by glial elements must also be considered. As for the mechanisms that operate by reducing outward cationic flow, a reduction in K+ conductance is mainly involved in membrane depolarization. Other ionic conductances of importance in epileptogenesis will relate most significantly to the reduction in synaptic inhibitory mechanisms, i.e. a reduction of GABAergic or glutaminergic synapses.

Rate-dependent effects of procainamide on His-Purkinje conduction in man.

Microelectrode studies in isolated cardiac tissues have shown that the depressant effect of several antiarrhythmic drugs on the maximal upstroke velocity of the cardiac action potential is rate-dependent. To determine whether this effect of antiarrhythmic drugs is seen in humans, 14 patients undergoing atrial pacing at several rates were prospectively studied before and after the infusion of procainamide (15 mg/kg). The HV interval (His-Purkinje conduction rate) and the QRS duration (intraventricular conduction rate) were measured. Before procainamide infusion, atrial pacing did not significantly prolong the maximal HV interval (from 54 +/- 15 to 58 +/- 13 ms). After procainamide infusion (mean serum level 10.0 +/- 3 micrograms/ml) atrial pacing at an average of 5 pacing rates significantly prolonged the HV interval (from 67 +/- 18 to 80 +/- 20 ms, p less than 0.001). The extent of HV prolongation with atrial pacing after procainamide infusion was independent of the HV interval at rest before procainamide. The duration of the QRS complex also tended to prolong with atrial pacing after procainamide infusion, but this prolongation was not statistically significant. Thus, procainamide produces a rate-dependent depressant effect on His-Purkinje and intraventricular conduction, confirming observations made in isolated tissue preparations.

Does seizure activity produce Purkinje cell loss?

Eight Wistar rats were exposed to 140 electroconvulsive seizures over 50 days. Ten rats served as controls. The density of Purkinje cells in cerebellum ranged from 15.3 to 18.5/mm in the treated rats and from 15.2 to 19.1/mm in the controls. No Purkinje cell loss was disclosed in the rats subjected to electroconvulsive seizures. Twenty-five Mongolian gerbils of the seizure-susceptible strain were selected according to seizure score with five animals in each group. Five Mongolian gerbils of a seizure-resistant strain served as controls. The density of the Purkinje cells ranged from 21.4 to 29.8/mm in the seizure-susceptible animals and from 27.6 to 31.5/mm in the controls, with a lower density in the gerbils with seizures compared with the controls (p less than 0.05). There was no relation to type or number of seizures. Eight gerbils of the seizure-susceptible strain were included as a supplementary group, to disclose any possible genetic trait as an explanation of the lower Purkinje cell density. The Purkinje cell density in these animals ranged from 24.8 to 30.9/mm and did not differ from the density in the seizure-resistant gerbils. Thus the lower density of Purkinje cells in the seizure-susceptible Mongolian gerbils is a result of seizure activity. The excessive epileptic input with stimulation of the glutamatergic innervation of the Purkinje cells resulting in a persistent elevated gamma-aminobutyric acid (GABA) tone may explain the damage to the Purkinje cells in the gerbils and the loss of Purkinje cells found in patients with severe epilepsy.

Physiological and histological effects of cerebellar stimulation.

Cerebellar implants have been placed in 62 patients with postoperative follow-up of 4 months to 3 years. Initially currents were applied through electrodes of alternate polarity on the superior surface of the cerebellar hemispheres and subsequently through negative electrodes on the superior surface to positive electrodes on the posterior surface. The amount of current required for clinical improvement was approximately the same as that required to significantly reduce the amplitude of the somatosensory evoked potential. The clinical and electrophysiological effects were proportional to the intensity of current and to the number of electrodes through which the currents were applied. Currents applied through the cerebellum were more effective than those confined near the cerebellar surface. Histological examination of the cerebellum from the chimpanzees and from 1 patient who died of causes unrelated to stimulation failed to demonstrate any evidence of neuronal damage related to application of current.

Cellular basis for reversal of hyperkalemic electrocardiographic changes by sodium.

We examined the hypothesis that reversal of hyponatremic hyperkalemic electrocardiographic changes through the infusion of saline solutions was due to the action of sodium ion in increasing the action potential rising velocity which is depressed when the cell is exposed to increasing concentrations of potassium. Using standard microelectrode techniques, the rising velocity of canine ventricular cells was shown to increase by 21%, whereas conduction time between two microelectrodes decreased 17% when the sodium concentration of the perfusate was increased from 120 to 163 mM in 2.7 mM potassium solution. When these cells were exposed to identical increases in sodium concentration in a 7.7-mM potassium solution, rising velocity increased 55% (P less than 0.005), whereas interelectrode conduction time decreased 33% (P less than 0.05). Similar changes were noted in experiments on human ventricular cells. These experimental findings are consistent with the hypothesis stated above.