NMDA receptor-mediated dendritic spikes and coincident signal amplification.

Dendrites of cortical neurons possess active conductances, which contribute to the nonlinear processing of synaptic information. Recently it has been shown that basal dendrites can generate highly localized spikes mediated by NMDA receptor channels. These spikes may serve as a powerful mechanism to detect and amplify synchronously activated spatially clustered excitatory synaptic inputs in individual dendritic segments, and may enable parallel processing in several integrative dendritic subunits.

NMDA spikes in basal dendrites of cortical pyramidal neurons.

Basal dendrites are a major target for synaptic inputs innervating cortical pyramidal neurons. At present little is known about signal processing in these fine dendrites. Here we show that coactivation of clustered neighbouring basal inputs initiated local dendritic spikes, which resulted in a 5.9 +/- 1.5 mV (peak) and 64.4 +/- 19.8 ms (half-width) cable-filtered voltage change at the soma that amplified the somatic voltage response by 226 +/- 46%. These spikes were accompanied by large calcium transients restricted to the activated dendritic segment. In contrast to conventional sodium or calcium spikes, these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge. The ionic mechanism of these NMDA spikes may allow 'dynamic spike-initiation zones', set by the spatial distribution of glutamate pre-bound to NMDA receptors, which in turn would depend on recent and ongoing activity in the cortical network. In addition, NMDA spikes may serve as a powerful mechanism for modification of the cortical network by inducing long-term strengthening of co-activated neighbouring inputs.

Discontinuation of antiepileptic drugs after successful epilepsy surgery.

OBJECTIVE: To evaluate the frequency and risk factors for seizure recurrence subsequent to antiepileptic drug (AED) withdrawal in patients who underwent surgical treatment for intractable partial epilepsy and were rendered seizure-free. METHODS: The outcome of discontinuation of AED medication was studied retrospectively in 210 consecutive patients who were rendered seizure-free after epilepsy surgery performed between 1989 and 1993. RESULTS: Medical therapy was reduced in 96 patients and discontinued in 84 patients. The seizure recurrence rate after complete AED withdrawal was 14% and 36% at 2 and 5 years. In contrast, only 3% and 7% of the 30 patients who did not alter AED treatment after surgery had recurrent seizures in the same time intervals. After AED discontinuation, seizures tended to recur more often in patients with normal preoperative MRI studies compared with those with focal pathology. However, this difference did not reach significance. Intraoperative electrocorticography, extent of surgical resection, postoperative EEG, and seizure-free duration after surgery were not predictive of seizure outcome after AED withdrawal. CONCLUSIONS: AED withdrawal was associated with seizure recurrence in a significant portion of patients rendered seizure-free by epilepsy surgery. Patients with a normal preoperative MRI study showed a tendency for higher seizure recurrence, whereas the duration of seizure-free postoperative AED treatment interval did not significantly influence the seizure recurrence rate. These results will prove useful in counseling patients about discontinuing AED treatment after successful epilepsy surgery.

Chronic intracranial EEG monitoring for localizing the epileptogenic zone: an electroclinical correlation.

PURPOSE: To evaluate the diagnostic yield and identify predictive factors of the surgical outcome in patients with intractable partial epilepsy undergoing chronic intracranial EEG monitoring (CIEM). METHODS: The clinical, magnetic resonance imaging (MRI) and electrophysiologic data of 108 patients that underwent CIEM were retrospectively reviewed. The discharge pattern and spatial extent of the initial ictal discharge were determined by blinded visual inspection and computerized analysis. RESULTS: The main predictive indicator for epilepsy surgery outcome in patients that underwent CIEM was the presurgical MRI findings. Most patients with hippocampal atrophy or complete lesionectomy were rendered seizure free after epilepsy surgery (83 and 80%, respectively), whereas only a small minority of patients with partial lesionectomy or no detected MRI lesion had seizure-free operative outcomes (21 and 22%, respectively). Multifocal independent initiation of the initial ictal discharge was associated with a poor surgical outcome. In contrast, the pattern and local spatial extent of the initial ictal discharge observed with CIEM failed to predict the surgical outcome. CONCLUSIONS: The main predictor of the surgical outcome in patients that underwent CIEM was the MRI findings, whereas CIEM had only limited use in localizing the epileptogenic zone in the absence of an MRI lesion. The reported findings indicate a low specificity of CIEM in defining the site of seizure onset, which in turn significantly impairs the reliability of CIEM in delineating the epileptogenic zone for epilepsy surgery. Further studies are required to define the indications and patient subpopulations who can benefit from CIEM before epilepsy surgery.

Characterization and comparison of local onset and remote propagated electrographic seizures recorded with intracranial electrodes.

PURPOSE: To compared the ictal discharge patterns between local onset and remote propagated electrographic seizures recorded with chronic intracranial electrodes. METHODS: The electrophysiological data from 88 consecutive patients who underwent chronic intracranial EEG monitoring were retrospectively reviewed. The early and late discharge patterns of electrographic seizures at local onset and distant propagated sites were determined by blinded visual inspection and computerized analysis. RESULTS: Four early and three late electrographic seizure patterns were observed at the local onset sites. The four early patterns consisted of a rhythmic discharge in the beta range ("beta buzz"), rhythmic alpha-theta activity, rhythmic sharp waves in the delta range, and an irregular spike discharge. The three distinct late-discharge patterns consisted of a late beta buzz, rhythmic sharp theta activity, and a rhythmic polyspike and wave discharge. At remote propagated sites, electrographic seizures could be divided into two different types according to their early discharge pattern. The first was unique to remote propagated electrographic seizures and consisted of a rhythmic theta-delta activity correlated with the concurrent activity at the local-onset site. The second remote initiation type consisted of patterns indistinguishable from the earlier discharge patterns recorded at the local onset site. CONCLUSIONS: The initial ictal discharge pattern recorded with intracranial electrodes can assist in differentiating local onset and remote propagated electrographic seizures, with rhythmic round theta-delta activity being unique to distant propagated sites. Nevertheless, the initial discharge of a subclass of remote propagated electrographic seizures consists of an independent pattern indistinguishable from that observed at local onset sites.

NMDA receptors amplify calcium influx into dendritic spines during associative pre- and postsynaptic activation.

Long-term potentiation (LTP) of synaptic strength can be induced by synchronous pre- and postsynaptic activation, and a rise in postsynaptic calcium is essential for induction of LTP. Calcium can enter through both voltage-dependent Ca2+ channels and NMDA-type glutamate receptors, but the relative contributions of these pathways is not known. We have examined this issue in layer V cortical pyramidal neurons, using focal flash photolysis of caged glutamate to mimic synaptic input and two-photon, laser-scanning microscopy to measure calcium levels in dendritic spines. Most of the calcium entry in response to glutamate alone was via voltage-dependent Ca2+ channels, and NMDA receptors accounted for less than 20% of total Ca2+ entry. When glutamate was paired with postsynaptic action potentials, however, the NMDA-receptor-dependent component was selectively amplified. The same is likely to occur during paired physiological pre- and postsynaptic activation, providing a mechanism for the input specificity and Hebbian behavior of LTP.

Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons.

1. Simultaneous whole-cell voltage and Ca2+ fluorescence measurements were made from the distal apical dendrites and the soma of thick tufted pyramidal neurons in layer 5 of 4-week-old (P28-32) rat neocortex slices to investigate whether activation of distal synaptic inputs can initiate regenerative responses in dendrites. 2. Dual whole-cell voltage recordings from the distal apical trunk and primary tuft branches (540-940 microns distal to the soma) showed that distal synaptic stimulation (upper layer 2) evoking a subthreshold depolarization at the soma could initiate regenerative potentials in distal branches of the apical tuft which were either graded or all-or-none. These regenerative potentials did not propagate actively to the soma and axon. 3. Calcium fluorescence measurements along the apical dendrites indicated that the regenerative potentials were associated with a transient increase in the concentration of intracellular free calcium ([Ca2+]i) restricted to distal dendrites. 4. Cadmium added to the bath solution blocked both the all-or-more dendritic regenerative potentials and local dendritic [Ca2+]i transients evoked by distal dendritic current injection. Thus, the regenerative potentials in distal dendrites represent local Ca2+ action potentials. 5. Initiation of distal Ca2+ action potentials by a synaptic stimulus required coactivation of AMPA- and NMDA-type glutamate receptor channels. 6. It is concluded that in neocortical layer 5 pyramidal neurons of P28-32 animals glutamatergic synaptic inputs to the distal apical dendrites can be amplified via local Ca2+ action potentials which do not reach threshold for axonal AP initiation. As amplification of distal excitatory synaptic input is associated with a localized increase in [Ca2+]i these Ca2+ action potentials could control the synaptic efficacy of the distal cortico-cortical inputs to layer 5 pyramidal neurons.

Activity-dependent action potential invasion and calcium influx into hippocampal CA1 dendrites.

The temporal and spatial profile of activity-evoked changes in membrane potential and intracellular calcium concentration in the dendrites of hippocampal CA1 pyramidal neurons was examined with simultaneous somatic and dendritic patch-pipette recording and calcium imaging experiments. Action potentials are initiated close to the soma of these neurons and backpropagate into the dendrites in an activity-dependent manner; those occurring early in a train propagate actively, whereas those occurring later fail to actively invade the distal dendrites. Consistent with this finding, dendritic calcium transients evoked by single action potentials do not significantly attenuate with distance from the soma, whereas those evoked by trains attenuate substantially. Failure of action potential propagation into the distal dendrites often occurs at branch points. Consequently, neighboring regions of the dendritic tree can experience different voltage and calcium signals during repetitive action potential firing. The influence of backpropagating action potentials on synaptic integration and plasticity will therefore depend on both the extent of dendritic branching and the pattern of neuronal activity.

Neuromuscular transmission in diabetes: response to high-frequency activation.

In searching for the cellular correlates of diabetic neuropathy, we examined the response to tetanic stimulation of diabetic neuromuscular junctions and of age-matched controls. The experiments were performed on the soleus nerve muscle preparation of the rat in which diabetes was induced by streptozotocin. Tetanic potentiation was substantially lower in diabetic rats. In addition, it was found that the diabetic neuromuscular junction is more resistant to high-frequency stimulation than normal age-matched controls, in which such stimulation causes a progressively increasing number of failures in synaptic transmission. Tetanic failures cannot be predicted from the stochastic properties of transmitter release and are due to propagation block of action potentials into the nerve terminals. The resistance of diabetic nerves to tetanic stimulation is a function of the duration of diabetes; the earliest significant difference between the number of tetanic failures in diabetic and normal age-matched controls was observed after 19 d of diabetes, and this difference grew with increased duration of diabetes. The resistance to tetanic stimulation in diabetic rats is reversed by insulin in vivo but not in vitro. Elevation in extracellular [K+] increases the number of tetanic failures in both diabetic and normal preparations. Furthermore, elevating extracellular [K+] to 8.5 mM brings the number of tetanic failures into the range of tetanic failures in normal nerves. This finding is consistent with the hypothesis that differences in extracellular [K+] accumulation during high-frequency stimulation are responsible for the diabetic nerve's relative resistance to high-frequency stimulation. The lower number of failures corrects only partially the impaired neuromuscular transmission in the diabetic state, and there is an overall reduction in tetanic potentiation in diabetes.

Pathophysiology of the neuromuscular junction in diabetic rats.

Using electrophysiological methods, we examined transport and transmission properties of the neuromuscular synapse in normal and diabetic rats. The stereospecific glucose transport system in the presynaptic nerve terminal was examined in two diabetic models and compared to the control. In both the streptozotocin (STZ) model and the Cohen model, a significant reduction was observed in the rates of glucose transport. A semiquantitative index for glucose transport, the glucose uptake factor, was 61 +/- 18% (SD) in the control group, 17 +/- 9% in the STZ group, and 15 +/- 10% in the Cohen group. Diabetes also affects the liberation of acetylcholine from the presynaptic motor nerve endings. The mean number of acetylcholine quanta liberated by the nerve impulse [quantal content (QC)] was reduced by 43% after 3.5 months of STZ diabetes. Thus, both the metabolic and the transmission functions of the neuromuscular junction are affected by the diabetic state.