Developmental neuroplasticity: roles in early life seizures and chronic epilepsy.

Both clinical and experimental studies suggest that the immature nervous system is unusually susceptible to seizures during critical periods in postnatal life. A late onset of gamma-aminobutyric acid (GABA)-mediated synaptic inhibition could conceivably play a contributing role in this phenomenon. Numerous studies have shown that neural systems that use GABA in the neonatal brain are different than those of adulthood. GABA is an excitatory neurotransmitter that likely plays a neurotrophic role in neuronal differentiation. Other reports suggest that unique, possibly transient, GABAergic interneuron populations exist in the embryonic and neonatal nervous system. At these early times in development, the immature nervous system is remarkably resistant to seizure generation. However, as the hippocampus and neocortex enter the critical period of enhanced seizure susceptibility, inhibitory GABA systems mature rapidly. At this time, blockade of GABA type A (GABAA) receptors produce unusually severe seizure discharges. In hippocampus, concurrent exuberant outgrowth of recurrent excitatory axon collaterals and synapses appear to play a role in the generation of these seizures. As the hippocampus matures, these axons are morphologically remodeled and nearly 50% of branches within arbors are pruned. This pruning of axon branches corresponds in time with the decrease in seizure susceptibility that characterizes adulthood. Developmental remodeling of neuronal connectivity is a common feature of most areas of the central nervous system. Results from an audiogenic seizure model of early onset epilepsy suggest that prevention of axon arbor remodeling by transient sensory deprivation can lead to a permanent overinnervation of target nuclei and chronic seizure susceptibility. Early life seizures may have a similar effect. Recent results in one model have shown that repeated seizures induced by intrahippocampal injections of tetanus toxin during a critical period results in a chronic epilepsy. Future studies should attempt to determine if the synchronized discharging of early-life seizures prevents the remodeling of neuronal connectivity that normally takes place during postnatal development and results in an overinnervated and chronically hyperexcitable hippocampus.

Audiogenic seizures induce c-fos in a model of developmental epilepsy.

In rats made susceptible to audiogenic seizures by exposing them to an intense noise at a critical time during development, subsequent noise exposure elicited seizures and induced the proto-oncogene c-fos in auditory regions of the brain. Cells showing Fos-like immunoreactivity were especially dense in dorsal and external cortices of the inferior colliculus, and were nearly absent after pretreatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. Noise exposure alone (i.e. no seizure) produced a localized zone of c-fos induction within the inferior colliculus, but only when presented during the time period when susceptibility to audiogenic seizures can be most effectively induced.

Ontogenetic features of audiogenic seizure susceptibility induced in immature rats by noise.

Although numerous models are currently used for systematic study of the mechanisms of epileptogenesis in mature brain, few animal models have been developed that allow similar explorations in the developing nervous system. One experimental model of epilepsy supports a premise that perinatal experience can lead to eventual seizure susceptibility, however. Audiogenic seizure (AGS) susceptibility can be induced during a critical developmental period in normal mice by auditory deprivation and therefore by cochlear trauma. We studied the developmental parameters that affect success of both induction and testing of AGS-susceptibility in the rat. Intense high-frequency noise exposure was used as the traumatizing agent. The Wistar rat strain used is inherently seizure-resistant because in greater than 400 trials, untreated rats have never exhibited susceptibility at any age. Although single prolonged exposures to high-intensity noise were administered to groups of rats at ages between postnatal days (PNDs) 12 and 36, PND 14 was the age when exposure was most likely to result in eventual seizure susceptibility. Furthermore, duration of initial exposure on PND 14 determined the rate of susceptibility when measured 2 weeks later. Accordingly, we noted that single noise exposures at an intensity of 125 dB and ranging between 6 and 10 min in duration induced susceptibility in 100% of rats tested on PND 28; nonetheless, seizures among the rats exposed for 8 min were the most severe. Typically, these seizures began as wild running attacks and were followed by tonic/clonic convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

A slow NMDA-mediated synaptic potential underlies seizures originating from midbrain.

After bath-perfusion with gamma-aminobutyric acid antagonists, slices of the rat's inferior colliculus were studied electrophysiologically. Synchronized epileptiform events were found to occur. The most prominent intracellular event was a sustained 30 mV depolarization which was pharmacologically and electrophysiologically characterized as an N-methyl-D-aspartate-mediated event. We propose that elicitation of this slow synaptic potential is the a priori basis of seizures arising in this midbrain nucleus.

Technology versus clinical evaluation for fluid management decisions in CABG patients.

An exploratory study was designed to determine whether data made available by a pulmonary artery catheter or data obtained by nonivasive clinical evaluation were used as a basis for fluid management decisions in stable coronary artery bypass graft patients approximately 18 hours postoperatively and beyond. The sample consisted of 40 fluid management decisions made on 33 patients. The data were collected on all of the factors that influenced the decision. In no instance was information provided by the pulmonary artery catheter used as a basis for a fluid management decision; only noninvasive clinical measures were influential. The study questions the prolonged use of this medical technology with its attendant cost and risk. Nurses' roles in managing technology are highlighted.

The sensitive period and optimum dosage for induction of audiogenic seizure susceptibility by kanamycin in the Wistar rat.

The incidence and severity of audiogenic seizures in kanamycin (KM)-treated rat pups, from a Wistar strain which is inherently seizure-resistant, was analyzed as a function of (a) postnatal age at the time of KM injection (i.p.) and (b) KM dosage. The vigor of the pinna reflex response on postnatal day (PND) 28 was correlated with (a) age at the time of injection, (b) dosage and (c) individual audiogenic seizure severity scores on PND 28 or PND 32. The data indicate that PNDs 9-12 are the developmental period when the rat has its greatest sensitivity to induction of susceptibility to audiogenic seizures by KM. The pinna reflex data suggest that cochlear vulnerability to KM intoxication is also greatest during this period. The optimum dosage for the induction of susceptibility was 100 mg/kg X 4 days. Use of higher doses resulted in a reduction of both incidence and severity of audiogenic seizures. The pinna reflex generally exhibited a supranormal vigor in animals having the most severe seizures. The behavioral attributes of induced audiogenic seizures at postnatal ages of 28 and 32 days are described and discussed.

Dopaminergic innervation of Aplysia gill muscle.

1. The fluorescence histochemical method of Hillarp and Falck was employed to investigate the distribution of dopamine in the gill of Aplysia. 2. Dopamine-containing nerve fibers and varicosities were found in close association with the lateral and medial external pinnule muscles, the circular and longitudinal muscles of the afferent vessel, and the circular muscles of the efferent vessel. 3. Other large, dopamine-containing, intensely fluorescent processes were observed lining the vascular sinuses of the gill and within the muscle bundles themselves. 4. Our findings support the hypothesis that dopamine is a neuromuscular transmitter in the gill. However, the data also suggest that dopamine may play a hormonal role as well.

Dopamine produces muscle contractions and modulates motoneuron-induced contractions in Aplysia gill.

1. Dopamine has been reported to exist in unusually large quantities in Aplysia gill. The physiological role of this neurotransmitter in this organ was examined. 2. The addition of dopamine to a gill perfusate results in the contractions of the lateral and medial external pinnule muscles, the circular and longitudinal muscles of the afferent vessel, and the circular muscles of the efferent vessel. 3. Dopamine-induced contractions persist after chemical synaptic transmission is eliminated in the gill. This suggests that excitatory dopamine receptors are present on gill smooth muscle fibers themselves. 4. Dopamine also potentiates the gill response to action potentials in single identified gill motoneurons. Evidence presented suggests that muscle contractions and modulation of motoneuron contractions are independent phenomena. 5. While modulation may in part be mediated by increases in excitatory junction potential (EJP) amplitude, in many cases large increases in muscle contractions occur while the enhancement of EJPs is disproportionately small. 6. Dopamine's ability to produce muscle contractions suggests that there may be dopaminergic motoneuron innervation of the gill. We suggest that dopamine's modulatory actions may be mediated via modification of excitation-contraction coupling in smooth muscle fibers.

Superoxide dismutase activity in the cochlea.

It was found that superoxide dismutase (SOD) exhibits a higher specific activity in a fraction of the cochlea that contains the organ of Corti than in most other neural tissues. SOD may comprise as much as 4.3% of the soluble protein in this fraction. Approximately 74% of this SOD is cyanide-inhibitable, indicating that it is the Cu/Zn isoenzyme usually found in the cytoplasm. SOD activity was also found in a fraction containing the stria vascularis. Two enzymes that regulate peroxide concentrations, catalase and glutathione peroxidase, were also prominent in both of these fractions.

Corresponding effects of acoustic fatigue on the cochlear microphonic and the compound action potential.

Moderate levels of acoustic fatigue, usually induced by a 100 dB SPL pure tone at a frequency appropriate to the location of intracochlear differential electrodes, have a surprising and paradoxical influence on the cochlear microphonic and the compound action potential of the auditory nerve. While the low-level microphonic becomes smaller, the low-level action potential becomes considerably larger and exhibits a shortened latency. The high-level microphonic and the high-level action potential are left virtually unchanged at these levels of fatigue. Nonetheless, if the duration or intensity of exposure is increased, both the high-level and low-level action potentials decrease as well. Assuming that the low-level microphonics are generated by outer hair cells, these data suggest that one relationship between outer hair cell function and neural function is inhibition at low intensities. Assuming that the high-level microphonic tends to be generated by inner hair cells, the decrease in the action potential at all intensities whenever the high-level microphonic potential is impaired suggests that the functional relationship between inner hair cells and auditory nerve function is excitatory.

Corresponding effects of hypoxia on the cochlear microphonic and the compound action potential.

Mild hypoxia has an unexpected influence on the compound action potential (CAP) compared to its effect on the cochlear microphonic (CM). While the CM decreases in amplitude near threshold, the low-level CAP increases in amplitude by as much as 400% and decreases in latency and width. The magnitude of latency decrease is dependent on the center frequency of 1/3 octave band-filtered clicks used as stimuli. Below 13 500 Hz the latency is increasingly shortened at a rate of 0.073 ms/octave. At high intensities moderate hypoxia has no effect on either the CM or the CAP. However, with more severe hypoxia the high-level CM also begins to deteriorate. Correspondingly both the high- and low-intensity CAP decrease in magnitude and increase in latency relative to their control values. Assuming that the low-level CM is generated by outer hair cells, these results suggest that one relationship between outer hair cell function and auditory nerve function near function near threshold is that of inhibition. The fact that N1 latency is shortened suggests that this inhibition occurs in the basalward direction.

Prophylaxis of kanamycin-induced ototoxicity by a radioprotectant.

S-2 (3-aminopropylamino)ethylphosphorothioate ameliorates hearing losses due to ototoxic doses of kanamycin sulfate in the guinea pig when administered one hour before the antibiotic. Since this radioprotectant is believed to operate as a free-radical scavenger, kanamycin ototoxicity may involve free radicals.

Noninvasive chronic recording of auditory nerve potentials.

A system is described which allows repeated, noninvasive recording of auditory nerve responses in the cat to transient acoustic stimuli using a closed acoustic system. N1 responses to clicks are recorded from a stainless steel ring electrode at the end of a hollow earbar, the tapered end of which is made of insulating plastic. Acoustic stimuli are generated by a dynamic earphone coupled to the earbar. A calibrated probe microphone is also imcorporated into the earbar to measure sound pressure near the tympanic membrane. This allows better stimulus control than is available with free-field systems. To facilitate insertion of the earbar, meatoplasties were performed on all animals. Responses recorded with this system in anesthetized cats are described and compared with those recorded at the round window. Good repeatability of measurements is described for an animal population of 20 domestic cats over a period of several months. For some of these animals, response amplitude varied from one session to another, but response latency, especially for condensation clicks, was consistent. By comparing statistics of multiple measurement of both N1 amplitude and latency for rarefaction and condensation clicks, it is concluded that the N1 latency vs click-level function for condensation clicks provides the most reliable measure of the cat's auditory nerve function.