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PubMed2001

Effects of testosterone on the electrical properties and nicotinic transmission of the major pelvic and coeliac ganglion neurones.

The effects of testosterone on the electrical properties and nicotinic activation of prevertebral ganglion neurones were investigated in vitro on the male rat major pelvic ganglion and rabbit coeliac ganglion. The electrical activity of the neurones was recorded using intracellular recording techniques. Nicotinic activation was triggered for neurones of the major pelvic ganglion by stimulating the hypogastric, pelvic and cavernous nerves and for coeliac neurones by stimulating the splanchnic nerves. Testosterone modified the resting membrane potential of neurones in the major pelvic ganglion by triggering a slow depolarization, and was without significant effect on the resting membrane potential of coeliac ganglion neurones. In neurones of the major pelvic and coeliac ganglia, testosterone had no significant effect on the firing pattern, on the characteristics of the action potential (firing threshold, duration, overshoot) and on the after-hyperpolarization (amplitude and duration). Testosterone affected, in opposite ways, the nicotinic activation of neurones of the two prevertebral ganglia. In the major pelvic ganglion, testosterone triggered an increase in the amplitude of excitatory postsynaptic potentials induced by stimulation of the hypogastric, pelvic and cavernous nerves with a single pulse, revealing a facilitation of nicotinic activation. On coeliac ganglion neurones, testosterone elicited a decrease in the amplitude of excitatory postsynaptic potentials induced by stimulation of the splanchnic nerves, indicating an inhibition of nicotinic activation. Our study shows that testosterone acts differently on neurones of prevertebral ganglia involved in the nervous control of different functions, its facilitatory action being exerted on neurones of the major pelvic ganglion which is particularly involved in the control of the urogenital tract. Our study reinforces the concept, derived from neuroanatomical and pharmacological studies, of the major pelvic ganglion as a major peripheral target for testosterone.

Animals↗

PubMed1997

Synaptic activation of Ca2+ action potentials in immature rat cerebellar granule cells in situ.

Although numerous Ca2+ channels have been identified in cerebellar granule cells, their role in regulating excitability remained unclear. We therefore investigated the excitable response in granule cells using whole cell patch-clamp recordings in acute rat cerebellar slices throughout the time of development (P4-P21, n = 183), with the aim of identifying the role of Ca2+ channels and their activation mechanism. After depolarizing current injection, 46% of granule cells showed Ca2+ action potentials, whereas repetitive Na+ spikes were observed in an increasing proportion of granule cells from P4 to P21. Because Ca2+ action potentials were no longer observed after P21, they characterized an immature granule cell functional stage. Ca2+ action potentials consisted of an intermediate-threshold spike (ITS) activating at -60/-50 mV and sensitive to voltage inactivation and of a high-threshold spike (HTS), activating at above -30 mV and resistant to voltage inactivation. Both ITS and HTS comprised transient and protracted Ca2+ channel-dependent depolarizations. The Ca2+ action potentials could be activated synaptically by excitatory postsynaptic potentials, which were significantly slower and had a proportionately greater N-methyl-D-aspartate (NMDA) receptor-mediated component than those recorded in cells with fast repetitive Na+ spikes. The NMDA receptor current, by providing a sustained and regenerative current injection, was critical for activating the ITS, which was not self-regenerative. Moreover, NMDA receptors determined temporal summation of impulses during repetitive mossy fiber transmission, raising membrane potential into the range required for generating protracted Ca2+ channel-dependent depolarizations. The nature of Ca2+ action potentials was considered further using selective ion channel blockers. N-, L-, and P-type Ca2+ channels generated protracted depolarizations, whereas the ITS and HTS transient phase was generated by putative R-type channels (R(ITS) and R(HTS), respectively). R(HTS) channels had a higher activation threshold and were more resistant to voltage inactivation than R(ITS) channels. At a mature stage, most of the Ca2+-dependent effects depended on the N-type current, which promoted spike repolarization and regulated the Na+-dependent discharge frequency. These observations relate Ca2+ channel types with specific neuronal excitable properties and developmental states in situ. Synaptic NMDA receptor-dependent activation of Ca2+ action potentials provides a sophisticated mechanism for Ca2+ signaling, which might be involved in granule cell development and plasticity.

Action Potentials↗

PubMed1986

Neurophysiology of limbic system pathways in the rat: projections from the amygdala to the entorhinal cortex.

We studied the responses of rat entorhinal neurons to electrical stimulation of the amygdala. Four main results were obtained: (1) excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation of the amygdala. Cells in layers II, III and V of the entorhinal cortex were responsive. (2) Excitatory responses were followed by inhibitory postsynaptic potentials. (3) Frequency potentiation of both excitatory and inhibitory responses was observed when 10/s stimulation was used. (4) Three amygdala neurons were antidromically activated by entorhinal stimulation; and two layer II entorhinal cells that were excited by amygdala stimulation were also antidromically activated by dentate gyrus stimulation. These results provide evidence for a monosynaptic, excitatory projection from the amygdala to the entorhinal cortex. In addition, the data indicate that amygdala neurons are only one synapse removed from the excitation of dentate gyrus granule cells.

Action Potentials↗

PubMed2002

The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.

Many central neurons possess large acid-activated currents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H(+)-gated currents in hippocampal neurons. Neuronal H(+)-gated currents and transient acidification are proposed to play a role in synaptic transmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in dendrites localized at synapses. Moreover, loss of ASIC impaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eyeblink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plasticity, learning, and memory.

Acid Sensing Ion Channels↗

PubMed1999

Comparative effects of methylmercury on parallel-fiber and climbing-fiber responses of rat cerebellar slices.

The environmental neurotoxicant methylmercury (MeHg) causes profound disruption of cerebellar function. Previous studies have shown that acute exposure to MeHg impairs synaptic transmission in both the peripheral and central nervous systems. However, the effects of MeHg on cerebellar synaptic function have never been examined. In the present study, effects of acute exposure to MeHg on synaptic transmission between parallel fibers or climbing fibers and Purkinje cells were compared in 300- to 350-microm cerebellar slices by using extracellular and intracellular microelectrode-recording techniques. Field potentials of parallel-fiber volleys (PFVs) and the associated postsynaptic responses (PSRs) were recorded in the molecular layer by stimulating the parallel fibers in transverse cerebellar slices. The climbing-fiber responses were also recorded in the molecular layer by stimulating white matter in sagittal cerebellar slices. At 20, 100, and 500 microM, MeHg reduced the amplitude of both PFVs and the associated PSRs to complete block, however, it blocked PSRs more rapidly than PFVs. MeHg also decreased the amplitudes of climbing-fiber responses to complete block. For all responses, an initial increase in amplitude preceded MeHg-induced suppression. Intracellular recordings of excitatory postsynaptic potentials of Purkinje cells were compared before and after MeHg. At 100 microM and 20 microM, MeHg blocked the Na+-dependent, fast somatic spikes and Ca++-dependent, slow dendritic spike bursts. MeHg also hyperpolarized and then depolarized Purkinje cell membranes, suppressed current conduction from parallel fibers or climbing fibers to dendrites of Purkinje cells, and blocked synaptically activated local responses. MeHg switched the pattern of repetitive firing of Purkinje cells generated spontaneously or by depolarizing current injection at Purkinje cell soma from predominantly Na+-dependent, fast somatic spikes to predominantly Ca++-dependent, low amplitude, slow dendritic spike bursts. Thus, acute exposure to MeHg causes a complex pattern of effects on cerebellar synaptic transmission, with apparent actions on both neuronal excitability and chemical synaptic transmission.

Action Potentials↗

PubMed2005

AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons.

Positive modulators of AMPA receptors enhance synaptic plasticity and memory encoding. Facilitation of AMPA receptor currents not only results in enhanced activation of excitatory neurons but also increases the activity of inhibitory interneurons by up-modulating their excitatory input. However, little is known about the effects of these modulators on cells other than pyramidal neurons and about their impact on local microcircuits. This study examined the effects of members from three subfamilies of modulators (mainly CX516, CX546 and cyclothiazide) on excitatory synaptic responses in four classes of hippocampal CA1 neurons and on excitatory and disynaptically induced inhibitory field potentials in hippocampal slices. Effects on excitatory postsynaptic currents (EPSCs) were examined in pyramidal cells, in two types of inhibitory interneurons located in stratum radiatum and oriens, and in stratum radiatum giant cells, a novel type of excitatory neuron. With CX516, increases in EPSC amplitude in pyramidal cells were two to three times larger than in interneurons and six times larger than in radiatum giant cells. The effects of CX546 on response duration similarly were largest in pyramidal cells. However, this drug also strongly differentiated between stratum oriens and radiatum interneurons with increases being four times larger in the latter. In contrast, cyclothiazide had similar effects on response duration in all cell types. In field recordings, CX516 was several times more potent in enhancing excitatory postsynaptic potentials (EPSPs) than feedback or feedforward circuits, as expected from its larger influence on pyramidal cells. In contrast, BDP-20, a CX546 analog, was more potent in enhancing feedforward inhibition than either EPSPs or feedback inhibition. This preference for feedforward over feedback circuits is probably related to its higher potency in stratum radiatum versus oriens interneurons. Taken together, AMPA receptor modulators differ substantially in their potency and/or efficacy across major classes of neurons which is likely to have consequences with regard to their impact on circuits and behavior.

Animals↗

PubMed2001

Impaired motor cortical inhibition in Parkinson's disease: motor unit responses to transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS)-induced corticospinal volleys can be investigated in detail by analysing the firing pattern modulation of active motor units (MUs) at close to threshold stimulation strengths. In amyotropic lateral sclerosis (ALS) these volleys are dispersed and prolonged, attributed to altered motor cortical excitability. Impaired intracortical inhibition, as found in ALS, is not unique to this disease, but is also a well-established finding in Parkinson's disease (PD). The present study explored whether reduced inhibition in the motor cortex in PD is accompanied by similar changes in motor unit firing modulation by TMS as are found in ALS. TMS was applied to the contralateral motor cortex during a low-force voluntary elbow flexion while 126-channel surface electromyography (SEMG) was recorded from the brachial biceps muscle. A recently developed method for SEMG decomposition was used to extract the firing pattern of up to five simultaneously active MUs. Sixteen MUs in 7 PD patients and 17 MUs in 5 healthy control subjects were analysed and peristimulus time histograms (PSTHs) and interspike interval change functions (IICFs) were calculated. The IICF provides an estimate of the modulation of the postsynaptic membrane potential at the spinal motoneuron, evoked by the stimulus. In PD the duration of the PSTH peak was significantly increased and the synchrony was decreased. The excitatory phase at 20-50 ms of the IICF was broader in PD, reflecting a longer duration of the TMS-evoked excitatory postsynaptic potential. It is proposed that these results are due to prolonged corticospinal volleys resulting from impaired intracortical inhibition.

Action Potentials↗

PubMed1997

Morphological and electrophysiological characterization of layer III cells of the medial entorhinal cortex of the rat.

Entorhinal cortex layer III cells send their axons into hippocampal area CA1, forming the less well studied branch of the perforant path. Using electrophysiological and morphological techniques within a slice preparation, we can classify medial entorhinal cortex layer III cells into four different types. Type 1 and 2 cells were projection cells. Type 1 cells fired regularly and possessed high input resistances and long membrane time constants. Electrical stimulation of the lateral entorhinal cortex revealed a strong excitation by both N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials. Type 2 cells accommodated strongly, had lower input resistances, faster time constants and featured prominent synaptic inhibition. Type 1 and 2 cells responded to repetitive synaptic stimulation with a prolonged hyperpolarization. We identified the two other, presumed local circuit, cell types whose axons remained within the entorhinal cortex. Type 3 cells were regular firing, had high input resistances and slow membrane time constants, while type 4 cells fired at higher frequencies and possessed a faster time constant and lower input resistance than type 3 neurons. Type 3 cells presented long-lasting excitatory synaptic potentials. Type 4 neurons were the only ones with different responses to stimulation from different sites. Upon lateral entorhinal cortex stimulation they responded with an excitatory postsynaptic potential, while a monosynaptic inhibitory postsynaptic potential was evoked from deep layer stimulation. In contrast to type 1 and 2 neurons, none of the local circuit cells could be antidromically activated from deep layers, and prolonged hyperpolarizations following synaptic repetitive stimulation were also absent in these cells. Together, the complementing morphology and the electrophysiological characteristics of all the cells can provide the controlled flexibility required during the transfer of cortical information to the hippocampus.

2-Amino-5-phosphonovalerate↗

PubMed1989

A mu-specific opioid peptide agonist increases excitability of pyramidal neurons in untreated and receptor up-regulated hippocampus.

The rat hippocampus contains the major types of opioid receptors, delta, mu, and kappa, as determined by autoradiographic and membrane binding analyses. Chronic exposure to excessive amounts of opioid antagonists results in a doubling of the number of binding sites. However, the direct electrophysiological significance of this increased number of opioid receptors in the central nervous system remains uncharacterized. We examined the effects of an opioid peptide with high affinity and high specificity for mu receptors, DAMGO (D-ala2-mePhe4-gly-ol5 enkephalin), under normal conditions and after 1 or 2 weeks of continuous infusion of the opiate antagonist naltrexone. Chronic infusion of naltrexone administered to the whole animal resulted in significant up-regulation (71%) of mu opioid receptors in the rat hippocampus. Slices of the hippocampus were perfused with artificial cerebrospinal fluid while recording population spikes in stratum pyramidale, excitatory postsynaptic potentials in stratum radiatum and while stimulating afferents in the Schaffer collaterals. Superfusion of slices with DAMGO produced a concentration-dependent increase in the amplitude of population spikes. No significant change was observed in the simultaneously recorded excitatory postsynaptic potential slope. This selective increase in population spike amplitude led to a leftward shift (19%) in the derived input-output curve. In addition, DAMGO superfusion produced extra spiking at higher stimulus intensities. Naltrexone reversed the DAMGO-induced increase in excitability, as well as prevented additional spikes. DAMGO superfusion of slices taken from chronically treated rats produced a much greater shift (42%) in the input-output curve than it did in untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1994

Endogenous adenosine deaminase does not modulate synaptic transmission in rat hippocampal slices under normoxic or hypoxic conditions.

Field and intracellular potentials were recorded from CA1 pyramidal stratum in submerged slices (at 33 degrees). During "normal" oxygenation (95% O2 + 5% CO2), tonic depression of population spikes and field excitatory postsynaptic potentials by endogenous adenosine was demonstrated by (i) the marked enhancement by the adenosine antagonists 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM), (ii) depression by the transport blocker dipyridamole (5 microM), and (iii) enhancement by exogenous adenosine deaminase (all tested by bath application). Thus, adenosine deaminase (0.5 units/ml) reduced by 10.7 +/- 3.0% (S.E.) the half-maximal stimulus intensity (for population spikes). The effects of adenosine deaminase were prevented by the specific inhibitor, deoxycoformycin (30 microM). In intracellular recordings, excitatory postsynaptic potentials were enhanced in a comparable manner by adenosine deaminase. By contrast, neither deoxycoformycin (5 and 30 microM) nor erythro-9-(2-hydroxy-3-nonyl)adenine (another adenosine deaminase inhibitor; 10 and 50 microM) had significant effects on population spikes. Superfusion with anoxic medium (saturated with 95% N2 + 5% CO2) for 2-3 min suppressed population spikes reversibly, by a mechanism involving adenosine, because 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM) delayed the onset of anoxic block and accelerated the subsequent recovery, and the recovery was much slower or incomplete in the presence of dipyramidole (0.5 microM). However, the anoxic suppression of population spikes was not affected by deoxycoformycin (30 microM) or erythro-9-(2-hydroxy-3-nonyl)adenine (10 microM); the corresponding 50% postanoxic recovery times were also unchanged (e.g. 4.0 +/- 0.2 min for controls and 4.1 +/- 0.3 min in deoxycoformycin).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1985

Facilitation and inhibition of nicotinic transmission by eserine in the sympathetic ganglia of the rabbit.

The effects of eserine on neurons and on ganglionic transmission of the isolated superior cervical ganglia of the rabbit were investigated by means of intracellular recording techniques. At the concentration of 10 microM or less, eserine reversibly increased the amplitude and duration of the fast excitatory postsynaptic potential (f-epsp) induced by preganglionic nerve stimulation and of the membrane depolarization evoked by iontophoretically-applied acetylcholine (ACh), but not carbachol. At the concentration of 50 microM or more, eserine consistently and reversibly depressed the fast excitatory postsynaptic potential as well as the depolarization induced by iontophoretic application of either ACh or carbachol. Furthermore, depolarization by ACh evoked in a low Ca/high Mg solution, which blocked the liberation of transmitter was similarly reduced by eserine in greater concentrations. The passive membrane properties of the sympathetic neurons were not significantly altered by eserine in the majority of neurons studied. The results indicate that the facilitatory action of eserine on ganglionic transmission may be explained by its anticholinesterase activity, whereas eserine-induced block of transmission appears to be related to a direct interaction between the compound and the postsynaptic ACh receptor-channel complex.

Acetylcholine↗

PubMed1988

Short-term exposure to bilirubin reduces synaptic activation in rat transverse hippocampal slices.

We evaluated the feasibility of using the in vitro transverse rat hippocampal slice as a model to study the effect of bilirubin on neuronal activity. Bilirubin in concentrations from 100 mumol/liter to 1 mmol/liter with bovine serum albumin as a stabilizer caused a significant decrease in the slope of the field excitatory postsynaptic potentials, concomitant with a significant increase in the peak latency of the population spike. These changes were partially reversible when bilirubin was removed from the incubation fluid. A partially reversible shift to the right of the presynaptic fiber volley/field excitatory postsynaptic potential relationship was interpreted as an expression of a reduction in synaptic activation. A partially reversible shift to the left of the field exitatory postsynaptic potential population spike relationship was interpreted as an expression of increased postsynaptic excitability. In conclusion the in vitro rat hippocampal slice was used successfully to study the effect of bilirubin on neuronal activity. A depressive effect of bilirubin was observed.

Action Potentials↗

PubMed1991

Chelation of postsynaptic Ca2+ facilitates long-term potentiation of hippocampal IPSPs.

In guinea pig hippocampal slices, a tetanic stimulation of the stratum radiatum caused long-term potentiation (LTP) of the excitatory postsynaptic potential (EPSP) but not of the GABAB receptor-mediated slow inhibitory postsynaptic potential (IPSP) in the CA1 neurons. In neurons in which Ca2+ was chelated with 1,2-bis(2-aminophenoxy) ethane N,N,N',N'-tetra-acetic acid (BAPTA) or ethylene-bis(oxyethylenenitrilo)tetra-acetic acid (EGTA), tetanic stimulation of the stratum radiatum caused LTP of the slow IPSP but not of the EPSP. These results indicate that a reciprocal relationship exists between LTP of the EPSP and LTP of the slow IPSP as far as the involvement of the postsynaptic Ca2+ is concerned.

2-Amino-5-phosphonovalerate↗

PubMed2003

Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1.

PURPOSE: To investigate further the membrane properties and postsynaptic potentials of the CA3 pyramidal cells in mice that display spontaneous seizures because of a targeted deletion of the Kcna1 potassium channel gene (encoding the Kv1.1 protein subunit). METHODS: Intracellular recordings were obtained from CA3 pyramidal cells in hippocampal slices prepared from Kcna1-null and control littermates. CA3 pyramidal cells were activated: orthodromically, by stimulating mossy fibers; antidromically, by activating Schaffer collaterals; and by injecting intracellular pulses of current. Responses evoked under these conditions were compared in both genotypes in normal extracellular medium (containing 3 mM potassium) and in medium containing 6 mM potassium. RESULTS: Recordings from CA3 pyramidal cells in Kcna1-null and littermate control slices showed similar membrane and action-potential properties. However, in 33% of cells studied in Kcna1-null slices bathed in normal extracellular medium, orthodromic stimulation evoked synaptically driven bursts of action potentials that followed a short-latency excitatory postsynaptic potential (EPSP)-inhibitory PSP (IPSP) sequence. Such bursts were not seen in cells from control slices. The short-latency gamma-aminobutyric acid (GABA)A-mediated IPSP event appeared similar in null and control slices. When extracellular potassium was elevated and excitatory synaptic transmission was blocked, antidromic activation or short pulses of intracellular depolarizing current evoked voltage-dependent bursts of action potentials in the majority of cells recorded in Kcna1 null slices, but only single spikes in control slices. CONCLUSIONS: Lack of Kv1.1 potassium channel subunits in CA3 pyramidal cells leads to synaptic hyperexcitability, as reflected in the propensity of these cells to generate multiple action potentials. The action-potential burst did not appear to result from loss of GABAA receptor-mediated inhibition. This property of CA3 neurons, seen particularly when tissue conditions become abnormal (e.g., elevated extracellular potassium), helps to explain the high seizure susceptibility of Kcna1-null mice.

Animals↗

PubMed2004

Blockade of Gi/o proteins modifies electrical activity of S-myenteric neurons from guinea-pig ileum.

We have investigated the effect of blockade of G(i/o) proteins on the electrical activity of S-myenteric neurons from guinea-pig ileum longitudinal muscle-myenteric plexus preparations. Intracellular recordings were made from either control or pertussis toxin (PTX) treated tissues. PTX is known to disrupt the function of G(i/o) proteins. Incubation with PTX (300 ng/ml) induced three main changes in the electrophysiological characteristics of S-neurons: (1) resting membrane potential was more depolarised; (2) fast excitatory postsynaptic potentials (EPSPs) were faster and narrower; and (3) spontaneous fast EPSPs and action potentials were more frequent. Amplitude of slow EPSPs was not modified. This general increase in excitability after blockade of G(i/o) proteins shares characteristics with the slow depolarisation induced by long-lasting trains of low-frequency electrical stimulation and could be mediated by similar mechanisms. Electrophysiological activity of S-myenteric neurons could be modulated by an inhibitory tone, which PTX could modify by either pre- or post-synaptic mechanisms, such as inhibition of the tonic release of inhibitory neurotransmitters and/or intracellular signal transduction involving PTX-sensitive G(i/o) proteins.

Animals↗

PubMed2003

Spike-dependent intrinsic plasticity increases firing probability in rat striatal neurons in vivo.

The collision of pre- and postsynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons.

4-Aminopyridine↗

PubMed1998

Frequency-dependent inhibition of neuronal activity by topiramate in rat hippocampal slices.

1. Topiramate is a structurally novel anticonvulsant which was recently approved for adjunctive therapy in partial and secondarily generalized seizures. The present study was aimed at elucidating the mechanisms underlying the anticonvulsant efficacy of topiramate using intra- and extracellular recording techniques in the in vitro hippocampal slices. 2. When stimuli were delivered every 20 s, topiramate had no measurable effect on both field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequency from 0.05-0.2 Hz, topiramate significantly decreased the slope of fEPSP and the amplitude of PS in a concentration-dependent manner. The amplitude of presynaptic fiber volley was also reduced. 3. Topiramate did not affect the magnitude of paired-pulse inhibition and monosynaptically evoked inhibitory postsynaptic potentials (IPSPs). 4. Sustained repetitive firing was elicited by injection of long duration (500 ms) depolarizing current pulses (500-800 pA). Superfusion with topiramate significantly reduced the number of action potentials evoked by a given current pulse. 5. After blockade of GABA receptors by bicuculline, burst firing which consisted of a train of several spikes riding on a large depolarizing wave termed paroxysmal depolarizing shift (PDS) was recorded. Application of topiramate reduced the duration of PDS and later spikes with less effect on the initial action potential. 6. These results suggest that frequency-dependent inhibition of neuronal activity due to blockade of Na+ channels may account largely for the anticonvulsant efficacy of topiramate.

Action Potentials↗

PubMed1997

Deafferentation weakens excitatory synapses in the developing central auditory system.

Decreased excitatory synaptic activity during development often leads to pre- and postsynaptic atrophy, as assessed anatomically. The present study considers the effect of decreased excitatory transmission on the maturation of synaptic strength. Towards this end, cochlear nucleus neurons, which project to the ipsilateral lateral superior olive (LSO), were denervated in gerbils at postnatal day 7, before the onset of hearing. This manipulation was intended to disrupt spontaneous glutamatergic transmission in the LSO while sparing the glycinergic afferents from the medial nucleus of the trapezoid body (MNTB). Afferent-evoked synaptic activity was assessed 1-6 days after ablation in a brain slice preparation using whole-cell current- and voltage-clamp recordings. In control animals, ipsilaterally evoked excitatory postsynaptic potentials (EPSPs) were present in 91% of neurons tested, but were observed in only 60% of neurons following cochlea removal. The maximum EPSP amplitude was significantly smaller in manipulated neurons compared with controls, and this was accompanied by a higher incidence of ipsilaterally evoked inhibitory postsynaptic potentials (IPSPs). To study the efficacy of excitatory synapses in greater detail, voltage-clamp recordings were made in the presence of strychnine and AP-5 [D(O)-2-amino-5-phosphonopentanoic acid]. The minimum excitatory postsynaptic current (EPSC) amplitude, presumed to reflect the efficacy of a single glutamatergic afferent, was approximately 40% smaller in manipulated neurons. In contrast, MNTB-evoked IPSPs were similar in neurons from control and ablated animals. However, manipulated neurons often exhibited a rebound depolarization after a hyperpolarizing current pulse or an afferent-evoked IPSP. In 70% of manipulated neurons, synaptically evoked rebound depolarizations were reduced, but not eliminated, by glutamate receptor antagonists. The glycine receptor antagonist strychnine did eliminate the IPSP-associated depolarization in these neurons. Collectively, these results suggest that functional denervation of excitatory afferents decreases their synaptic efficacy as result of both cell loss as well as decreased strength of individual surviving synapses.

Acoustic Stimulation↗