Strong paired pulse depression of dentate granule cells in slices from patients with temporal lobe epilepsy.

Recurrent, feedback excitation by sprouted mossy fibers may contribute to the hyperexcitability observed in human temporal lobe epilepsy. Observations in rodent models of epilepsy mimic the findings in human tissue and reveal that dentate granule cells sprout axons which innervate fibers in their own dendritic layer. However, recent evidence in rodents suggest that these sprouted fibers may form connections which cause inhibition of dentate granule cells, not excitation. Thus, the net effect of sprouting in human epileptic tissue may not only be recurrent excitation. We analyzed paired pulse depression in dentate slices from 9 patients with temporal lobe epilepsy and found evidence for strong feedback inhibition. We also noted failure of high frequency stimulation induced inhibition in our human specimens. These data challenge the concept that human epileptic dentate granule cells are excited by recurrent mossy fiber sprouting.

Evidence for physiologically active axonal adenosine receptors in the rat corpus callosum.

Several neurotransmitter receptors have been identified on axons, and emerging evidence suggests that central axonal conduction may be modulated by neurotransmitters. We have recently demonstrated the presence of extra-synaptic adenosine Al receptors along rat hippocampal axons. We now present immunocytochemical evidence for Al receptors on rat corpus callosum axons and show that these receptors actively modulate axon physiology. Using rat brain coronal slices, we stimulated the corpus callosum and recorded the evoked extracellular compound action potential. The lipid-soluble, Al-specific adenosine receptor agonist cyclopentyladenosine, dose-dependently decreased the compound action potential amplitude, an effect reversed by the specific Al antagonist 8-cyclopentyl-1, 3-dipropylxanthine. These data provide the first direct evidence that axonal Al adenosine receptors modulate axon physiology in the adult mammalian brain. Influencing axonal transmission is a potentially powerful mechanism of altering information processing in the nervous system.

Axillary somatosensory evoked potential response: an alternate peripheral recording site.

When recording upper-extremity somatosensory evoked potentials (SSEP), the standard peripheral recording site is Erb's point located near the clavicle. During some surgical procedures, the Erb's point recording site is often either part of the surgical field or is distorted by patient size or trauma. In the present study, we evaluated the usefulness of the axillary fossa as an alternate peripheral recording site. Using standard recording techniques, we studied 29 patients (54 limbs); studied: 19 as outpatients and 10 during surgery. Evoked responses subsequent to median nerve stimulation were recorded with the following montage: Axi-Axc, Epi-Epc, C5S-Cz or Fz, and Cpi-Cpc. The potential recorded at the axillary site, termed axillary response (Ax), produced a waveform similar in morphology to that of the Erb's point response and displayed a generally well defined, prominent negative peak occurring approximately 2.5 ms earlier than that of Erb's point. We conclude that the axillary space in the lateral part of the upper chest and medial side of the arm is an appropriate alternate site for recording peripheral potentials after stimulation of the median nerve. The Ax recording site is useful during surgery when the Erb's point site is unavailable. Further study of this recording site is necessary to determine its diagnostic usefulness.

Adenosine A1 receptors are located predominantly on axons in the rat hippocampal formation.

The nucleoside adenosine exerts potent biological effects via specific receptors, including the inhibitory A1 adenosine receptor (A1AR). In the hippocampus A1ARs play an important role in regulating neuronal activity. However, the cellular sites of hippocampal A1ARs are undefined. Using in situ hybridization, receptor autoradiography, and single- and double-label immunocytochemistry techniques, we have characterized the cellular sites of A1AR expression in the rat hippocampus. In situ hybridization and receptor autoradiography studies revealed strikingly different patterns of labeling. In situ hybridization studies revealed heaviest labeling of cell bodies in the granular layer of the dentate gyrus and the pyramidal layers of Ammon's horn. In contrast, using [3H]DPCPX, we observed heavy specific labeling over the neuropil in the dentate hilus stratum moleculare, stratum lacunosum-moleculare, stratum radiatum, and stratum oriens, and little labeling over cell bodies. Using single-label immunocytochemistry, A1AR immunoreactivity was found to be heaviest over fibers in regions corresponding with heavy [3H]DPCPX labeling. Double-label florescent confocal microscopy was then used to determine the identity of labeled fibers. A1AR immunoreactivity was found to co-localize with SMI-31 that labels axons, but not with MAP2a,b that labels cell bodies and dendrites, or with synaptophysin that labels synapses. These data identify axons as the predominant site of A1AR expression in hippocampus. Activation of A1ARs may be a powerful mechanism by which adenosine alters axonal transmission to inhibit neurotransmitter release.

The pathophysiology of human mesial temporal lobe epilepsy.

The correlation between clinical epilepsy and pathologic changes in the hippocampus was recognized in the early 1800s. However, the study of hippocampal pathology remained an anatomically descriptive discipline until the mid 1970s. In 1976, exploration of the electrical characteristics of the epileptic hippocampus and temporal neocortex began with the application of in vitro electrophysiologic techniques to human brain slices. Subsequently, recognition of the importance of neurotransmitters in epilepsy prompted ligand binding studies of receptor distributions in the epileptic brain. Recent refinements of DNA isolation and immunocytochemical techniques have led to the explosive development of antibodies to receptors, neurotransmitters, enzymes, and neurotransmitter transport systems. Since the 1980s, several alterations in epileptic hippocampus have been discovered with use of these pharmacologic and biochemical tools. The combination of anatomic, electrophysiologic, and biochemical experimental approaches has led to valuable insights into epilepsy-associated changes in temporal lobe tissue and has increased our understanding of the pathophysiology of temporal lobe epilepsy. Most of the summarized data in this review were derived from tissue excised from patients with medically intractable temporal lobe epilepsy or from postmortem brain. Although no attempt was made to cover the vast literature on animal models of epilepsy, some animal studies are discussed to illustrate current hypotheses that aid in the interpretation of the human findings.

Seizure-associated speech arrest in elderly patients.

Recurrent, brief episodes of speech arrest associated with bifrontal electroencephalographic seizure activity developed in three ill elderly patients. The seizures ceased after the initiation of antiepileptic drug therapy and the correction of metabolic abnormalities. The cause of the seizure activity remains unknown, but a possible mechanism may be a transient epileptogenic cortical dysfunction that predominantly affects the frontal lobes as a result of concomitant metabolic alterations.

Effects of the muscarinic antagonists pirenzepine and gallamine on spontaneous and evoked responses of rat cerebral cortical neurones.

1. The muscarinic receptor antagonists gallamine and pirenzepine were iontophoretically applied to rat cerebral cortical cholinoceptive neurones, including corticospinal neurones, to assess their effects on spontaneous firing, and firing induced by: stimulation of the nucleus basalis magnocellularis (NBM); contralateral hindpaw stimulation; application of acetylcholine (ACh); and application of glutamate. 2. Both compounds potently inhibited firing induced by ACh iontophoresis, whilst neither compound consistently altered firing induced by application of glutamate. 3. Gallamine was very effective and pirenzepine less effective, at inhibiting both spontaneous firing and the delayed firing induced by NBM stimulation. The short-latency excitations elicited by NBM stimulation were enhanced by these muscarinic antagonists. 4. Gallamine and pirenzepine enhanced cortical cholinoceptive cell firing induced by contralateral hindpaw stimulation. 5. It is concluded that gallamine depresses spontaneous activity more than pirenzepine, and that both compounds can affect the cortical cell firing evoked by stimulation of the NBM and of thalamo-cortical afferent fibres.

Nifedipine: more than a calcium channel blocker.

Nifedipine exhibits a greater incidence of side effects than the other currently marketed calcium channel antagonists. In addition to those effects attributable to calcium channel blockade, nifedipine produces side effects similar to the effects of adenosine. It is probable that nifedipine exerts part of its physiological actions through potentiation of adenosine. Adenosine, an endogenous calcium channel blocker, modifies synaptic events throughout the nervous system and causes sedation, smooth and skeletal muscle relaxation, anticonvulsion, hypotension and hypothermia, all reversible by caffeine or theophylline administration. Nifedipine inhibits adenosine uptake from, and release into, the extracellular space and binds at an adenosine receptor. Both nifedipine and adenosine interact with benzodiazepine binding sites. Interaction between nifedipine and adenosine should be kept in mind when treating patients with nifedipine.

Anticonvulsant effects of adenosine analogues on amygdaloid-kindled seizures in rats.

Male Long-Evans rats were stereotaxically implanted with a bipolar electrode in the central amygdala and with a stainless-steel cannula in the lateral cerebral ventricle. Rats were then kindled once daily until 3 consecutive Stage 5 kindled seizures were elicited. Adenosine analogues were injected into the lateral cerebral ventricle to examine their effects on behavioral seizures and afterdischarge duration following a kindling stimulus. 5'-N-ethylcarboxamidoadenosine (NECA) and (-)-N-(1-methyl-2-phenylethyl)-adenosine(L-phenylisopropyladenosine) (L-PIA) produced dose-related reductions of amygdaloid-kindled seizures with NECA exhibiting slightly more potent anticonvulsant activity than L-PIA. Parenteral injections of caffeine, at a dose which had no effect on seizure parameters, antagonized the anticonvulsant effects of NECA. These results are consistent with the notion that adenosine is a modulator of synaptic activity in the CNS and methylxanthines exert a specific antagonism of central adenosine receptors.

Interactions between adenosine and nifedipine in the rat cerebral cortex.

Nifedipine inhibits the uptake of [(3)H]adenosine into rat cerebral cortical synaptosomes with an IC(50) value of 1.1 ?M. When applied by iontophoresis onto rat cerebral cortical neurons it potentiated the depressant effects of adenosine on spontaneous firing. Some of the calcium-antagonist actions of nifedipine may be mediated by adenosine.