Synaptic and nonsynaptic contributions to giant ipsps and ectopic spikes induced by 4-aminopyridine in the hippocampus in vitro.

Hippocampal slices bathed in 4-aminopyridine (4-AP, < or =200 microM) exhibit 1) spontaneous large inhibitory postsynaptic potentials (IPSPs) in pyramidal cells, which occur without the necessity of fast glutamatergic receptors, and which hence are presumed to arise from coordinated firing in populations of interneurons; 2) spikes of variable amplitude, presumed to be of antidromic origin, in some pyramidal cells during the large IPSP; 3) bursts of action potentials in selected populations of interneurons, occurring independently of fast glutamatergic and of GABA(A) receptors. We have used neuron pairs, and a large network model (3,072 pyramidal cells, 384 interneurons), to examine how these phenomena might be inter-related. Network bursts in electrically coupled interneurons have previously been shown to be possible with dendritic gap junctions, when the dendrites were capable of spike initiation, and when action potentials could cross from cell to cell via gap junctions; recent experimental data showing that dendritic gap junctions between cortical interneurons lead to coupling potentials of only about 0.5 mV argue against this mechanism, however. We now show that axonal gap junctions between interneurons could also lead to network bursts; this concept is consistent with the occurrence of spikelets and partial spikes in at least some interneurons in 4-AP. In our model, spontaneous antidromic action potentials can induce spikelets and action potentials in principal cells during the large IPSP. The probability of observing this type of activity increases significantly when axonal gap junctions also exist between pyramidal cells. Sufficient antidromic activity in the model can lead to epileptiform bursts, independent of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, in some principal cells, preceded by IPSPs and spikelets. The model predicts that gap junction blockers should suppress large IPSPs observed in 4-AP and should also reduce the probability of observing antidromic activity, or bursting, in pyramidal cells. Experiments show that, indeed, the gap junction blocking compound carbenoxolone does suppress spontaneous large IPSCs, occurring in 4-AP plus ionotropic glutamate blockers, together with a GABA(B) receptor blocker; carbenoxolone also suppresses large, fast inward currents, corresponding to ectopic spikes, which occur in 4-AP. Carbenoxolone does not suppress large depolarizing IPSPs induced by tetanic stimulation. We conclude that in 4-AP, axonal gap junctions could, at least in principle, account in part for both the large IPSPs, and for the antidromic activity in pyramidal neurons.

Presence of gamma-aminobutyric acid transporter mRNA in interneurons and principal cells of rat hippocampus.

After release, neurotransmitters are removed from the extracellular space by high-affinity uptake. Specific sodium-dependent transporters serve this function for the inhibitory transmitter gamma-aminobutyric acid (GABA). However, it is largely unknown to which proportion GABA is taken up by GABAergic interneurons, glia cells or principal neurons. We analyzed the distribution of mRNA for the main GABA-transporter subtype in the hippocampus, GAT-1, in adult rats. Most interneurons were strongly stained for GAT-1 mRNA, indicating re-uptake by the GABA-releasing cells. Surprisingly, prominent signals for GAT-1 were also found throughout the principal cell layers (granule and pyramidal cells). These data indicate that GABA transporters may be present in non-GABAergic projection cells of the rat hippocampus which contribute to the clearance of GABA from the extracellular space.

Age-dependence of the anticonvulsant effects of the GABA uptake inhibitor tiagabine in vitro.

Epileptic syndromes frequently start at childhood and therefore it is crucial to test new anticonvulsants at immature stages of the nervous system. We compared the effects of the gamma-aminobutyric acid (GABA) uptake inhibitor tiagabine [(R)-N-(4, 4-bis(3-methyl-2-thienyl)but)3-en-1-yl nipecotic acid] on low-Mg(2+)-induced epileptic discharges in brain slices from rat pups (p 5-8) and juvenile animals (p 15-20). In tissue from rat pups, tiagabine slightly reduced epileptiform activity in hippocampal area CA1 but had no effect in the entorhinal cortex. In juvenile rats, epileptiform discharges were unaffected in CA1 but suppressed by 60% in the entorhinal cortex. While tiagabine increases its efficacy with age, in-situ hybridisation and PCR analysis show that mRNA coding for the neuronal GABA-transporter GAT-1 is already present at p 5. We therefore conclude that the increasing efficacy of tiagabine during ontogenesis is due to functional maturation of GABAergic synapses rather than to up-regulation of GAT-1 expression.

[Angiography for chorion carcinoma (author's transl)]. / Angiographie beim Chorionkarzinom.

The epidemiology, frequency and behaviour of hydatidiform moles, chorion adenomas and chorion carcinomas are summarised. The importance of angiography is stressed and illustrated by two examples. The value of the early correct diagnosis for the success of chemotherapy is pointed out.