Multiple mechanisms underlie burst firing in rat midbrain dopamine neurons in vitro

Both apamin and NMDA evoke burst firing in dopamine neurons recorded intracellularly in slices of rat midbrain. However, apamin-induced bursting required injection of depolarizing currents, and was mimicked by Bay K8644 and blocked by nifedipine. In contrast, NMDA-induced bursting required hyperpolarizing currents and was not blocked by nifedipine. Our results show that burst firing can be evoked in dopamine neurons via two different mechanisms.     

Iontophoretically administered drugs acting at the N-methyl-D-aspartate receptor modulate burst firing in A9 dopamine neurons in the rat.

Extracellular single-unit recording and iontophoresis were used to examine the effect of N-methyl-D-aspartate (NMDA) and the competitive NMDA antagonist (+/-)-4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) on the firing rate and firing pattern of A9 dopamine (DA) neurons in the rat. Administration of NMDA produced a dose-dependent increase in firing rate (up to nearly 300% of baseline at the highest ejection current), which could be blocked by iontophoretic CPP. Low currents (less than 10 nA) were sufficient to induce apparent depolarisation inactivation in some neurons. In addition to this effect on firing rate, NMDA also caused a dramatic increase in burst firing, which was also dose dependent; cells made more bursts, and each burst consisted of more spikes. The only measured aspect of burst morphology that was not affected was the mean burst interspike interval. All nonbursting cells (n = 10) were converted to burst firing by the drug. CPP administered alone was found to reduce burst firing, without affecting the firing rate. These data suggest that a tonically active excitatory amino acid input to A9 DA neurons is responsible for inducing burst firing in vivo and that this input seems to operate via the NMDA receptor, possibly by virtue of its link to a Ca2+ ionophore.     

SK channel blockade promotes burst firing in dorsal raphe serotonergic neurons

Previous in vivo studies have shown that blockade of small-conductance Ca(2+)-activated potassium (SK) channels enhances burst firing in dopaminergic neurons. As bursting has been found to be physiologically relevant for the synaptic release of serotonin (5-HT), we investigated the possible role of SK channels in the control of this firing pattern in 5-HT neurons of the dorsal raphe nucleus. In these cells, bursts are usually composed of doublets consisting of action potentials separated by a small interval (< 20 ms). Both in vivo and in vitro extracellular recordings were performed, using anesthetized rats and rat brain slices, respectively. In vivo, the specific SK blocker UCL 1684 (200 microm) iontophoresed onto presumed 5-HT neurons significantly increased the production of bursts in 13 out of 25 cells. Furthermore, the effect of UCL 1684 persisted in the presence of both the GABA(A) antagonist SR 95531 (10 mm) and the GABA(B) antagonist CGP 35348 (10 mm), whereas these agents by themselves did not significantly influence the neuronal firing pattern. In vitro, bath superfusion of the SK channel blocker apamin (300 nm) induced bursting in only three out of 18 neurons, although it increased the coefficient of variation of the interspike intervals in all the other cells. Our results suggest that SK channel blockade promotes bursting activity in 5-HT neurons via a direct action. An input which is present only in vivo seems to be important for the induction of this firing pattern in these cells.     

Activation of N-methyl-d-aspartate Receptors Induces Endogenous Rhythmic Bursting Activities in Nucleus Tractus Solitarii Neurons: An Intracellular Study on Adult Rat Brainstem Slices

A brainstem slice preparation and intracellular recording techniques were used to examine the effects of N-methyl-d-aspartate (NMDA) application on neurons within the swallowing area of the nucleus tractus solitarii (NTS). According to their cellular properties, NTS neurons were classified into type I and type II neurons. The most striking difference was the occurrence of delayed excitation in type I but not in type II neurons, when they were depolarized from membrane potentials more negative than -60 mV. Bath application of NMDA (30 - 60 microM) elicited depolarization and triggered stable repetitive firing in all the NTS neurons but one. During the NMDA-induced depolarization, hyperpolarization below -60 mV elicited, in some type I neurons, a rhythmic bursting pattern. The duration of the bursts (300 - 1000 ms) and their frequency (0.5 - 2 Hz) depended on the membrane potential. With hyperpolarizations below -75 mV, rhythmic bursting was converted into rhythmic single discharges, a pattern elicited directly in the other type I neurons. In all cases, rhythmic patterns were superimposed on cyclic depolarizations of the membrane potential characterized by an initial ramp-shaped phase. In type II neurons, rhythmic bursting discharges, superimposed on rhythmic oscillations of the membrane potential, were also obtained upon hyperpolarization during the NMDA-induced depolarization. In all type I neurons tested, NMDA-induced cyclic ramp-shaped depolarizations continued after addition of tetrodotoxin to the medium. Rhythmic bursting was not elicited by bath application of kainate (10 - 20 microM). Application of d-2-amino-5-phosphonovalerate (50 microM) blocked NMDA-induced depolarizations without modifying those elicited by kainate, which were selectively depressed by 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM). Moreover, removal of Mg2+ from the medium suppressed NMDA-induced cyclic depolarizations. Results demonstrate that both NMDA and non-NMDA receptors are present in NTS neurons and that selective activation of NMDA receptors induced rhythmic bursting and/or rhythmic single discharges. Rhythmic patterns were not driven by synaptic mechanisms but originated from endogenous properties of NTS neurons activated by NMDA. Thus, NTS neurons can be considered as conditional pacemakers. According to the location of the neurons, the conditional properties shown in these in vitro experiments might be involved in vivo in the generation of rhythmic motor activities set up at the NTS level, such as swallowing.     

GABAA receptor stimulation blocks NMDA-induced bursting of dopaminergic neurons in vitro by decreasing input resistance.

The effects of the GABAA agonist, isoguvacine, on NMDA-induced burst firing of substantia nigra dopaminergic neurons were studied with intracellular and whole cell recordings in vitro. NMDA application caused the neurons to fire in rhythmic bursts. Although the NMDA-induced bursty firing pattern was insensitive to hyperpolarization by current injection, it was reversibly abolished by the selective GABAA agonist, isoguvacine. The block of the rhythmic burst pattern by isoguvacine application occurred regardless of whether the chloride reversal potential was hyperpolarizing (ECl-=-70 mV) or depolarizing (ECl-=-40 mV). In either case, the input resistance of the dopaminergic neurons was dramatically decreased by application of isoguvacine. It is concluded that GABAA receptor activation by isoguvacine disrupts NMDA receptor-mediated burst firing by increasing the input conductance and thereby shunting the effects of NMDA acting at a distally located generator of rhythmic burst firing.     

Developmental Study of N-Methyl-d-Aspartate-induced Firing Activity and Whole-cell Currents in Nucleus Tractus Solitarii Neurons

Whole-cell recordings of rat nucleus tractus solitarii (NTS) neurons were performed on a slice preparation. We investigated possible postnatal changes in firing activities and currents induced by N -methyl- d -aspartate (NMDA) application. A total of 42 neurons were selected and fell into the following age groups: 0-5 days ( n = 15), 10-15 days ( n = 9) and 30-60 days (adult, n = 18). During this period, input resistance and spike duration decreased by-˜40%. At all ages, bath application of NMDA elicited a bursting firing activity when the membrane potential was held between -60 and -75 mV. However, in the youngest cells the rhythmic bursting activity was irregular and was characterized by a progressive firing inactivation during a burst. In a tetrodotoxin-containing saline, NMDA-induced oscillations of membrane potential were retained in all age groups. The membrane current-voltage relationship of the NMDA-induced inward current (I_NMDA) was characterized by a region of negative slope conductance which was similar in all age groups. Thus the voltage-dependent block of I_NMDA is present in NTS neurons from birth, allowing NTS neurons to display membrane potential oscillations. However, postnatal maturation of repolarizing conductances, as suggested by changes in spike characteristics, could render the oscillatory activity more stable than at birth.     

Burst Firing in Gonadotrophin‐Releasing Hormone Neurones does not Require Ionotrophic GABA or Glutamate Receptor Activation

Burst firing is a feature of many neuroendocrine cell types, including the hypothalamic gonadotrophin‐releasing hormone (GnRH) neurones that control fertility. The role of intrinsic and extrinsic influences in generating GnRH neurone burst firing is presently unclear. In the present study, we investigated the role of fast amino acid transmission in burst firing by examining the effects of receptor antagonists on bursting displayed by green fluorescent protein GnRH neurones in sagittal brain slices prepared from adult male mice. Blockade of AMPA and NMDA glutamate receptors with a cocktail of CNQX and AP5 was found to have no effects on burst firing in GnRH neurones. The frequency of bursts, dynamics of individual bursts, or percentage of firing clustered in bursts was not altered. Similarly, GABA_A receptor antagonists bicuculline and picrotoxin had no effects upon burst firing in GnRH neurones. To examine the importance of both glutamate and GABA ionotrophic signalling, a cocktail including picrotoxin, CNQX and AP5 was used but, again, this was found to have no effects on GnRH neurone burst firing. To further question the impact of endogenous amino acid release on burst firing, electrical activation of anteroventral periventricular nuclei GABA/glutamate inputs to GnRH neurones was undertaken and found to have no impact on burst firing. Taken together, these observations indicate that bursting in GnRH neurones is not dependent upon acute ionotrophic GABA and glutamate signalling and suggest that extrinsic inputs to GnRH neurones acting through AMPA, NMDA and GABA_A receptors are unlikely to be required for burst initiation in these cells.     

Glutamatergic input governs periodicity and synchronization of bursting activity in oxytocin neurons in hypothalamic organotypic cultures

During suckling, oxytocin (OT) neurons display a bursting electrical activity, consisting of a brief burst of action potentials which is synchronized throughout the OT neuron population and which periodically occurs just before each milk ejection in the lactating rat. To investigate the basis of such synchronization, we performed simultaneous intracellular recordings from pairs of OT neurons identified retrospectively by intracellular fluorescent labelling and immunocytochemistry in organotypic slice cultures derived from postnatal rat hypothalamus. A spontaneous bursting activity was recorded in 65% of OT neurons; the remaining showed only a slow, irregular activity. Application of OT triggered bursts in nonbursting neurons and accelerated bursting activity in spontaneously bursting cells. These cultures included rare vasopressinergic neurons showing no bursting activity and no reaction to OT. Bursts occurred simultaneously in all pairs of bursting OT neurons but, as in vivo, there were differences in burst onset, amplitude and duration. Coordination of firing was not due to electrotonic coupling because depolarizing one neuron in a pair had no effect on the membrane potential of its partner and halothane and proprionate did not desynchronize activity. On the other hand, bursting activity was superimposed on volleys of excitatory postsynaptic potentials (EPSPs) which occurred simultaneously in pairs of neurons. EPSPs, and consequently action potentials, were reversibly blocked by the non-NMDA glutamatergic receptor antagonist CNQX. Taken together, these data, obtained from organotypic cultures, strongly suggest that a local hypothalamic network governs synchronization of bursting firing in OT neurons through synchronous afferent volleys of EPSPs originating from intrahypothalamic glutamatergic inputs.     

Voltage- and Ca2+-dependent burst generation in neuroendocrine Dahlgren cells in the teleost Platichthys flesus

The neuroendocrine Type 1 Dahlgren cells of the caudal neurosecretory system of the flounder display characteristic bursting activity, which may increase secretion efficiency. The firing activity pattern in these cells was voltage-dependent; when progressively depolarized, cells moved from silent (approximately -70 mV), through bursting and phasic to tonic firing (< -65 mV). Brief (10 s) evoked bursts of spikes were followed by a slow after-depolarization (ADP; amplitude up to 10 mV, duration 10-200 s), which was also voltage-dependent and could trigger a prolonged burst. The ADP was significantly reduced in the absence of external Ca(2+) ions or the presence of the L-type Ca(2+) channel blocker, nifedipine. BayK 8644 (which increases L-type channel open times) significantly increased ADP duration, whereas the Ca(2+)-activated nonselective cation channel blocker, flufenamic acid, had no effect. Pharmacological blockade of Ca(2+)-activated K(+) channels, using apamin and charybdotoxin, increased the duration of both ADP and evoked bursts. However, action potential waveform was unaffected by either apamin/charybdotoxin, nifedipine, BayK 8644 or removal of external Ca(2+). The short duration (approximately 100 ms), hyperpolarization-activated, postspike depolarizing afterpotentials (DAP), were significantly reduced by nifedipine. We propose that long duration ADPs underlie bursts and that short duration DAPs play a role in modulation of spike frequency.     

Gamma-aminobutyric acid(B) receptor activation suppresses stimulus-evoked burst firing in rat substantia nigra reticulata neurons

Previous whole-cell patch-pipette studies showed that focal electrical stimulation of the subthalamic nucleus (STN) evokes a long-lasting complex excitatory postsynaptic currents (EPSC) and synaptically evoked bursts of action potentials in substantia nigra pars reticulata (SNR) neurons. Although synaptically evoked bursting may play a role in normal physiology, excessive burst firing correlates with symptoms of Parkinson's disease. We used patch-pipette recordings in rat brain slices to study the effects of baclofen on complex EPSCs and STN-induced burst firing in SNR neurons. Baclofen (1 μM) caused a reversible, 73% reduction in complex EPSCs, and this effect was blocked by the γ-aminobutyric acid(B) antagonist CGP35348 (100 μM). Using the loose-patch method to record extracellular potentials, a lower concentration of baclofen (100 nM) inhibited STN-evoked bursts, while leaving spontaneous firing of action potentials less affected. We suggest that strategies that selectively inhibit burst firing in the SNR might have therapeutic potential in the treatment of Parkinson's disease.     

Two distinct types of repetitive bursting activity mediated by NMDA in hypothalamic neurons in vitro

Hypothalamic magnocellular dorsal nucleus neurons were recorded from adult guinea pig brain slices with the whole-cell patch-clamp technique to determine the effects of N-methyl-D-aspartate (NMDA) applied in the bath or by iontophoresis. In a majority of cells (59 of 77, 76.6%), rhythmic bursting discharges were evoked by specific activation of NMDA receptors when the membrane was more negative than -60 mV. This endogenous rhythmic activity was resistant to tetrodotoxin. It was suppressed by removal of extracellular Mg2+, indicating the involvement of the voltage-dependent block of the NMDA channel by Mg2+. Application of thapsigargin showed that rhythmic activity did not depend on the release of Ca2+ from reticulum stores. Blockers of Ca2+ conductances Ni2+ and nifedipine had no effects on the bursts. Their repolarization did not involve the activation of a strophantidin- or ouabain-sensitive pump, but partly depended on an apamine-sensitive Ca2+-dependent K+current. In a small subset of cells (9 of 69, 13%), specific activation of NMDA receptors induced another type of bursting activity which consisted of repetitive low-threshold spikes sustaining bursts of action potentials. Rhythmic low-threshold spikes subsisted in the presence of tetrodotoxin but were suppressed by Ni2+. Increasing the amount of NMDA brought about a switch from the rhythmic low-threshold spike burst firing to the rhythmic bursting activity observed for the majority of cells. The present data show for the first time that NMDA receptor activation can induce two independent rhythmic bursting behaviours in the same neuron, probably depending on the strength of the glutamatergic drive.     

Determinants of neuronal firing pattern in the guinea-pig subthalamic nucleus: Anin vivo andin vitro comparison

Summary To ascertain the extent to which neuronal firing pattern in the subthalamic nucleus (STN) is determined by afferent inputs, a comparison was made between STN neurons recordedin vivo andin vitro (a largely denervated preparation).In vivo, the majority of cells exhibited an irregular firing pattern, although some showed evidence of burst firing. In contrast, all cells had a regular firing patternin vitro. Electrical stimulation of the striatopallidal complexin vivo induced a short latency inhibition in STN neurons, followed by a burst of spikes. These effects could be reproducedin vitro; hyperpolarising pulses gave rist to a slow depolarising potential upon termination, which was accompanied by a burst of action potentials. Hence, the evidence suggests that afferents play an important role in determining the firing pattern of STN neurons. Howerver, the cells also possess intrinsic membrane properties which allow inputs to trigger either single spikes or bursts.     

Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity.

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker-like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: 1) a 20-50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst-like pattern, and 2) a short-latency inhibition lasting 5-25 msec in 75% of non-DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30-60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two-fold increase in burst firing 6-14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6-14 minutes. Muscimol-induced STN inhibition produced complimentary biphasic changes in SN neuron firing: 1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and 2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: 1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and 2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents.     

Competitive NMDA receptor antagonists differentially affect dopamine cell firing pattern

Alterations in the firing pattern of mesencephalic dopamine (DA) neurons appear to constitute a physiological mechanism through which these cells modify their effects on target neurons. Several lines of evidence suggest that the activity patterns exhibited by DA cells in vivo are contingent on tonic activation of N-methyl-D-aspartate (NMDA) receptors. In the present series of experiments, extracellular single unit recording techniques were used to assess the effects of the centrally acting, competitive NMDA receptor antagonists CGS-19755, (±)-CPP, NPC-12626 and NPC-17742 on the firing properties of nigral DA neurons in the chloral hydrate-anesthetized rat. Each of the drugs tested produced a modest increase in firing rate accompanied by a significant regularization of neuronal firing pattern. Although the number of bursts and the percentage of spikes in bursts were reduced, the proportion of cells operationally defined as bursting was not appreciably altered. This appeared to be due to the ability of these drugs to reduce the number of spike doublets without affecting the incidence of longer bursts. Although generally consistent with the notion that NMDA receptors modulate DA neuronal firing pattern, the present data do not support the contention that tonic activation of these receptors is solely responsible for the expression of bursting activity in vivo. Synapse 25:234–242, 1997. © 1997 Wiley-Liss, Inc.     

GABAA receptor stimulation blocks NMDA-induced bursting of dopaminergic neurons in vitro by decreasing input resistance

The effects of the GABA_A agonist, isoguvacine, on NMDA-induced burst firing of substantia nigra dopaminergic neurons were studied with intracellular and whole cell recordings in vitro. NMDA application caused the neurons to fire in rhythmic bursts. Although the NMDA-induced bursty firing pattern was insensitive to hyperpolarization by current injection, it was reversibly abolished by the selective GABA_A agonist, isoguvacine. The block of the rhythmic burst pattern by isoguvacine application occurred regardless of whether the chloride reversal potential was hyperpolarizing (E_Cl⁻=−70 mV) or depolarizing (E_Cl⁻=−40 mV). In either case, the input resistance of the dopaminergic neurons was dramatically decreased by application of isoguvacine. It is concluded that GABA_A receptor activation by isoguvacine disrupts NMDA receptor-mediated burst firing by increasing the input conductance and thereby shunting the effects of NMDA acting at a distally located generator of rhythmic burst firing.     

The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease

Dexmedetomidine (an alpha‐2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep‐brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A ‘Dex bolus’ group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a ‘no sedation’ group (29 cells from 11 patients). We also performed within‐patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke–Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike‐oscillations analysis(beta peak, P = 0.4; signal‐to‐noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high‐dose dexmedetomidine should be avoided during DBS surgery.     

Complex EPSCs evoked in substantia nigra reticulata neurons are disrupted by repetitive stimulation of the subthalamic nucleus

Although substantia nigra reticulata (SNR) neurons fire bursts of action potentials during normal movement, excessive burst firing correlates with symptoms of Parkinson's disease. A major excitatory output from the subthalamic nucleus (STN) to the SNR is thought to provide the synaptic impetus for burst firing in SNR neurons. Using patch pipettes to record from SNR neurons in rat brain slices, we found that a single electrical stimulus delivered to the STN evokes a burst of action potentials. Under voltage-clamp conditions, STN stimulation evokes a complex EPSC that is comprised of an initial monosynaptic EPSC followed by a series of late EPSCs superimposed on a long-lasting inward current. Using varied stimulation frequencies, we found that the initial EPSC was significantly reduced or abolished after 2 s of 50-100 Hz STN stimulation. However, only 4 s of 1 Hz stimulation was required to abolish the late component of the complex EPSC. We suggest that differential effects of repetitive STN stimulation on early and late components of complex EPSCs may help explain the frequency-dependent effects of deep brain stimulation of the STN that is used in the treatment of Parkinson's disease.     

Burst firing of oxytocin neurons in male rat hypothalamic slices

Burst firing and single spike activity play different roles in the modulation of local neuronal circuit activity and neurosecretion. In hypothalamic oxytocin (OT) neurons in vivo, burst firing is associated with pulsatile secretion of OT in the milk ejection reflex, and can be observed in slices from both immature and lactating rats in vitro. Whether OT neurons from male rats also possess burst firing capability is still an open question. To examine this possibility, whole-cell patch clamp recordings were made in supraoptic nucleus OT neurons in brain slices from male rats. In low Ca(2+) medium, the alpha(1)-adrenoceptor agonist, phenylephrine evoked bursts that were highly similar to those from lactating rats in vivo and in vitro: explosive onset, short-duration, quickly reaching peak firing rate and displaying an exponential decay in returning to the pre-burst rate. During bursts, spike durations increased, and spike amplitudes decreased, while riding on an arc of depolarization around peak rate. In comparison to those from lactating rats in vitro, the rising phase of male bursts was more rapid, the decay phase was slower, and the rising phase of the spike after hyperpolarization was faster. No significant differences, however, were seen in burst characteristics that are most important in determining the amount of peptide release: burst amplitudes (the number of spikes in a burst), firing frequency within bursts or peak firing rate. Thus, we conclude that OT neurons in males are capable of burst firing highly similar to that seen in lactating rats.     

Unrelated course of subthalamic nucleus and globus pallidus neuronal activities across vigilance states in the rat

The pallido-subthalamic pathway powerfully controls the output of the basal ganglia circuitry and has been implicated in movement disorders observed in Parkinson's disease (PD). To investigate the normal functioning of this pathway across the sleep-wake cycle, single-unit activities of subthalamic nucleus (STN) and globus pallidus (GP) neurons were examined, together with cortical electroencephalogram and nuchal muscular activity, in non-anaesthetized head-restrained rats. STN neurons shifted from a random discharge in wakefulness (W) to a bursting pattern in slow wave sleep (SWS), without any change in their mean firing rate. This burst discharge occurred in the 1-2 Hz range, but was not correlated with cortical slow wave activity. In contrast, GP neurons, with a mean firing rate higher in W than in SWS, exhibited a relatively regular discharge whatever the state of vigilance. During paradoxical sleep, both STN and GP neurons increased markedly their mean firing rate relative to W and SWS. Our results are not in agreement with the classical 'direct/indirect' model of the basal ganglia organization, as an inverse relationship between STN and GP activities is not observed under normal physiological conditions. Actually, because the STN discharge pattern appears dependent on coincident cortical activity, this nucleus can hardly be viewed as a relay along the indirect pathway, but might rather be considered as an input stage conveying corticothalamic information to the basal ganglia.     

Epileptiform bursts elicited in CA3 hippocampal neurons by a variety of convulsants are not blocked by N-methyl-d-aspartate antagonists

Intracellular and extracellular recordings from CA₃ hippocampal neurons in vitro were used to study the ability of several NMDA (N-methyl-d-aspartate) receptor antagonists to suppress epileptiform bursts induced by NMDA and convulsants not thought to act at NMDA receptors. The antagonists, APV (d-2-amino-5-phosphonovalerate), AP-7 (d,l-2-amino-7-phosphonoheptanoate) and CPP (d,l-3-[(±)-2-car☐ypiperazin-4-yl-]-propyl-1-phosphonic acid), blocked the spontaneous and evoked bursts induced by NMDA. CPP, but not APV or AP-7, prevented the development of bursts induced by Mg-free medium. The NMDA antagonists failed to block bursting induced by kainate, 7 mM K⁺, mast cell degranulating peptide, anoxia or spontaneous bursting. In some cases the NMDA antagonists induced spontaneous bursts or enhanced burst frequency, a proconvulsant effect. It is concluded that activation of NMDA receptors is sufficient but not necessary for burst generation in the CA₃ region.