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Neurocomputing 70 (2007) 1619–1625

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Depolarizing, GABA-mediated synaptic responses and their possiblerole in epileptiform events; Simulation studies

Richard Robertson�, Kerstin M.L. Menne

Department of Mathematics and Statistics, California State Polytechnic University, 3801 W. Temple Avenue, Pomona, CA 91768, USA

Available online 3 November 2006

Abstract

Synaptic transmission controlled by the release of the inhibitory neurotransmitter GABA is generally considered to be the mechanism

by which glutamate-mediated excitation is kept under control in the human hippocampus and neocortex. Until recently, epilepsy was

thought of as a simple imbalance of neuronal excitation and inhibition. This theory of epileptogenesis has been challenged by the finding

that GABA does not always inhibit neuronal activity. Although in adult brain GABA usually induces hyperpolarization of cell

membranes, in juvenile brain GABA is depolarizing, bringing the neuronal membrane closer to firing threshold, often enabling action

potentials to be triggered. Somewhat surprisingly, GABA-mediated synaptic responses in adult brain tissue can sometimes be excitatory,

too.

Cohen et al. [I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, R. Miles, On the origin of interictal activity in human temporal lobe

epilepsy in vitro, Science 298 (2002) 1418–1421] discovered a subpopulation of excitatory projection cells that exhibited depolarizing

GABA responses in slices from epileptic adult subiculum. While most subicular pyramidal cells displayed hyperpolarized behavior in

response to GABA, some actually fired bursts of action potentials, in synchrony with the interneurons; the GABA released by the

interneurons was only depolarizing for this subset of excitatory cells.

These results suggest that it is the interaction between excitatory projection cells depolarized by GABA and interneurons that initiates

epileptiform events, at least in subiculum. Interneurons usually seem to provide an inhibitory shield around excitatory neurons.

However, when connected to projection cells responding ‘abnormally’ to GABA with depolarization, they may promote paroxysmal

synchronizations.

A summary of some recent theories and results is presented on possible causes and effects of depolarizing, GABA-mediated synaptic

responses in the cerebrum. Special attention is focused on the hippocampal/parahippocampal formation, especially the subicular

complex. The subiculum seems to be of particular interest because of its strategic output location to neocortex, and because of the

spontaneous, interictal-like activity observed almost exclusively there in slices from patients suffering mesial temporal lobe epilepsy.

Simulation results follow, starting from a commonly known GENESIS computer model of a small part of CA3. This ‘CA3’ was re-

modeled to more closely resemble a small, ‘subiculum-like’ structure, with a complement of fast-spiking interneurons and three types of

projection cells: ‘strong-bursting’, ‘weak-bursting’, and ‘regular-spiking’. Parametric studies of the effects of increasing EGABAA; the

GABA reversal potential of certain GABAA receptors, simulate the sometimes excitatory impact of GABAergic signaling. The effects of

GABAB receptor impairment in this setting are also briefly considered. Results presented here reinforce experimental evidence that the

subiculum has ‘‘the right stuff’’ to play a significant role in epileptiform events.

r 2006 Elsevier B.V. All rights reserved.

Keywords: GABA; Subiculum; Temporal lobe epilepsy; KCC2

1. Introduction

A summary of some recent theories and results ispresented on possible causes and effects of depolariz-

e front matter r 2006 Elsevier B.V. All rights reserved.

ucom.2006.10.053

ing author. Tel.: +1909 9852524.

ess: NeuroCyclist1@aol.com (R. Robertson).

ing, GABA-mediated synaptic responses in the cere-brum. Special attention is focused on the hippocampalformation and parahippocampal region, especially thesubicular complex. The subiculum seems to be of particularinterest because of its strategic output location toneocortex, and because of the spontaneous, interictal-likeactivity observed almost exclusively there in slices from

ARTICLE IN PRESSR. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–16251620

patients suffering mesial temporal lobe epilepsy (MTLE)[4,23].

Although in adult brain GABA usually induces hyper-polarization of cell membranes, in juvenile brain GABA isdepolarizing, i.e., it brings the neuronal membrane closerto firing threshold, often enabling action potentials to betriggered. Somewhat surprisingly, GABA-mediated synap-tic responses in adult brain tissue can sometimes beexcitatory, too [5].

2. ‘Excitatory’ GABA

Evidence suggesting that GABA may play an excitatoryrole in synaptic integration in adult cortex has beenprovided by complementary lines of research. Andersenet al. [1] first demonstrated the efficacy of prolonged,dendritically applied GABA in promoting action potentialgeneration in hippocampal pyramidal (pyr) cells. ThenMartina et al. [5] showed the same for somatic applicationto mature neocortical pyramids.

Cohen et al. [4] discovered a subpopulation of excitatoryprojection cells that exhibited depolarizing GABA re-sponses in slices from epileptic adult subiculum, part of thehippocampal formation of the brain’s temporal lobes.While most of the subicular pyr cells displayed hyperpo-larized behavior in response to GABA, some of themactually fired bursts of action potentials, in synchrony withthe interneurons. These results suggest that it is theinteraction between excitatory projection cells depolarizedby GABA and interneurons that initiates epileptiformevents, at least in subiculum.

They studied slices excised from patients with chronic,intractable MTLE. MRI and scalp or intracranial EEGsconfirmed that all seizures originated in the temporal lobe.Cohen’s group rarely observed spontaneous spiking in thesclerotic CA3 or CA1 regions, or in the dentate gyrus.However, large, spontaneous extracellular spikes, reminis-cent of interictal epileptiform activity, were always detectedin the subiculum, which then vanished in the entorhinalcortex (EC). In all slices examined, this interictal-likeactivity occurred rhythmically and synchronously atsubicular sites up to 5mm apart; the synchronousdischarging continued even when the subiculum wassurgically isolated.

As had been anticipated, the interictal-like dischargesthey had observed were blocked by applying glutamatergicreceptor antagonists such as NBQX, CNQX, and APV.But, somewhat unexpectedly, GABAA receptor antagonistssuch as bicuculline and picrotoxin were also found tosuppress these epileptiform events.

The interneurons fired action potentials both before andduring population bursts, but subpopulations of the pyrcells exhibited qualitatively different behaviors. While 78%of the pyr neurons displayed inhibited, hyperpolarizedbehavior in response to GABAergic stimulation byinterneurons, the remaining 22% were actually ‘excited’by the GABA they received. These excited pyr cells

participated with the interneurons in generating interictal-like population bursts. They, too, fired both before andduring the epileptiform activity and, together with theinterneurons, seemed to act as ‘‘pacemaker cells’’ ingenerating the synchronous, paroxysmal events. Cohen etal. concluded that both glutamatergic and GABAergicsignaling were involved, and that the distinction betweenpyr cells which discharged and those which were inhibiteddepended mainly on their different GABAergic reversalpotentials. Interestingly, the subpopulation of pyr neuronsresponding ‘abnormally’ to GABA with depolarizationvaried over time, suggesting that different cells can take onthis role as circumstances change the neuronal environ-ment.Deisz [7] commented that he had also observed such

spontaneous discharging corresponding to interictal activ-ity in neocortical slices from TLE patients. A number ofresearchers have likewise demonstrated that such interictal-like events can also occur spontaneously in animal modelsof TLE, also suggestive of an ‘excitatory’ role for GABA.In the 4-aminopyridine (4AP) rodent model, for instance,these epileptiform discharges are usually preceded by large,GABA-mediated postsynaptic potentials [2], which areapparently caused by synchronous burst-firing of theinterneurons [14]. This interictal-like population activitywould seem to be mainly the result of GABA-mediatedrecurrent excitation [13,25].

3. Possible mechanisms of GABAergic excitation

It has been widely reported in the literature [10,22] thatthe effectiveness and even the qualitative nature (depolar-izing vs. hyperpolarizing) of GABAergic transmission areinfluenced by the neuronal expression of the K+/Cl�

protein cotransporter KCC2, which extrudes chloride. Inparticular, Deisz [7] speculated that the depolarizingGABAA response in human epileptogenic tissue may resultfrom the nexus of reduced KCC2 expression, the equipoiseof chloride gradient and membrane potential, and thepartial bicarbonate permeability of GABAA channels. It isknown that KCC2 expression in adult rat neurons isreduced following epileptiform activity and/or neuronaldamage.Gulledge and Stuart [8] noted that the expression of

KCC2 in maturing pyr neurons leads to lower intracellularchloride levels [22]. Thus, activation of GABAA receptorsshould cause an inward flow of negatively charged chlorideions. But, using cation-specific, gramicidin-based patchrecordings, they also found the GABAA reversal potential,EGABAA

, to be about 10mV depolarized to restingmembrane potential (RMP). They then raised the naturalquestion of how neurons that actively extrude chloride ionscould exhibit depolarizing, GABAA receptor-mediatedresponses. Their answer was that GABAA receptors arealso permeable to the bicarbonate anion HCO3

�, whosepermeability is only fractionally that of the chloride ion

ARTICLE IN PRESSR. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–1625 1621

[12], but whose driving force in the opposite, depolarizingdirection is significantly greater.

Deisz [7] made two interesting observations that supportthe speculation that KCC2 may play a crucial role inrefractory epilepsies: (1) seizure activity is induced bymetabolic disorders that cause an elevation of cerebralammonium levels, possibly due to impaired K+/Cl�

transport; (2) whereas TLE patients often present a historyof febrile convulsion, temperature elevation can cause adepolarizing shift of the GABA reversal potential ofcortical neurons, also compatible with reduced K+/Cl�

transport.

4. The subiculum and TLE

The subiculum serves as the chief output structure of thehippocampal formation, and it projects to various corticaland subcortical targets, including EC, perirhinal cortex,amygdala, and thalamus. Primarily innervated by CA1 pyrcell axons, it also receives numerous projections from manyother cortical and subcortical regions [3].

Menendez de la Prida et al. [18] noted that the subicularcomplex (consisting of subiculum, presubiculum, andparasubiculum) has been implicated in neurological dis-orders such as schizophrenia and Alzheimer’s disease.Furthermore, Menendez de la Prida [16] pointed out theinvolvement of the hippocampal-subicular-entorhinalpathway in TLE, as seen in animal studies [9] and inhuman investigations [4,11].

Recently, Benini and Avoli [3] used slices extending fromhippocampus to EC bathed in 4AP to induce a type of TLEin rats, in order to investigate the role of the subiculum insynchronous, epileptiform events. They saw that little or nosubicular activity was evoked by electrical stimulation ofCA1 under control conditions, with never any response inEC. On the other hand, after application of the GABAA

receptor antagonist picrotoxin, strong discharges could beelicited in the subiculum, which then spread to EC.Moreover, they showed that the picrotoxin-bathed sub-iculum generated synchronous, low-amplitude dischargeseven when surgically isolated from adjacent structures.However, in subicular tissue first bathed in 4AP, thosedischarge patterns were drastically altered after subsequentapplication of picrotoxin; in their place, vigorous networkbursting occurred. These results suggest that the subiculumis important in regulating hippocampal output, largely viaGABAA receptor mediation, and that this gating controlsinteractions involved in seizure modulation.

5. Classification of subicular neurons

Menendez de la Prida [16] classified cells from the ratsubicular complex as intrinsically-bursting (IB), regular-spiking (RS), or fast-spiking (FS) neurons electrophysio-logically, from their responses to depolarizing somaticcurrent pulses at RMP. Anatomical examination showedthat the IB and RS types were characteristic of projection

cells and that the FS cells corresponded to interneurons. Asis customary, IB cells that fired more than one burst inresponse to these current pulses were classified as strong-bursting, ‘IB+’, whereas those that fired only one burstwere labeled as weak-bursting, ‘IB�’.

6. Simulation model

We first chose Kerstin Menne’s GENESIS computermodel of a small, CA3-like structure [19,20] as our ‘‘lumpof clay.’’ We then attempted to modify this ‘CA3’ assimply, yet effectively, as possible to reflect some of themore important attributes of a human ‘subiculum-like’structure.

7. Menne’s CA3 model

Menne modeled her ‘CA3’ by a small network consistingof 72 simulated pyr cells, plus 9 feedforward (ff) and 9feedback (fb) interneurons.Her pyr cell model was originally described by Traub et

al. [26]. The GENESIS implementation of Traub’s modelcomprises 66 compartmental building blocks, representingsoma, apical and basal dendrites, and the axon itself. Sixtypes of voltage and/or ligand-dependent ion channels gotincorporated into this cell model: one for sodium (Na+),one for calcium (Ca2+), and four different varieties forpotassium (K+). This wide array of voltage-, time-, and/orconcentration-dependent channels provides these cells a‘fast’ sodium current, a high-threshold calcium current, adelayed-rectifier potassium current, a transient potassiumcurrent, a calcium-dependent potassium current, and anafterhyperpolarization (AHP), calcium-dependent potas-sium current. Menne’s 72 pyr cells all derive from the samemodel; they only differ in their three-dimensional positionsin the network. Including the synaptically activatedchannels, each pyr cell model has 317 conductive channels.In reality, excitatory input to CA3 pyr cells originates fromperforant path fibers from EC and from mossy fibers, theaxons of granule cells of dentate gyrus. Menne simulatedthis input by random excitation, via arrays of GENESISrandomspike elements. In addition, she implementedrecurrent excitation among pyr cells.Menne’s interneuron model was also described by Traub

[24]. It was originally implemented in GENESIS byMenschik [21], but Menne [19] made some modificationsto it. As a result, her simulated interneurons have 48compartments and 214 conductive channels. For simulat-ing fb and ff interneurons, the same model was used; theyonly differ in their connectivities. fb interneurons receivetheir excitatory input from pyr cells, while ff interneuronsreceive random excitatory input, representing stimulationfrom Schaffer collaterals or perforant path fibers. Connec-tions from interneurons onto pyr cells represent inhibitoryinput from bistratified cells, basket cells, and chandeliercells found in the CA3 region. Menne did not implementmutual inhibitory connections among the interneurons.

ARTICLE IN PRESS

Fig. 1. CSR as a function of increasing EGABAAexfor the IBs cells.

R. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–16251622

The synaptically activated channels were modeled to beAMPA, NMDA, GABAA, or GABAB receptor-mediated,as originally implemented in GENESIS for a granule cellmodel developed at the Laboratory of Theoretical Neuro-biology, University of Antwerp.

8. Modeling a subiculum-like structure

Based largely on the work of Menendez de la Prida[16,18], we modified Menne’s single pyramidal cell model,pyr, to simulate the three most basic projection cell types ofthe subiculum: the IB�, the IB+, and the RS. In theabsence of a low-threshold calcium channel model in theavailable GENESIS software, we decided to maintain amostly common assortment of cell parameters for allprojection cells. There were very few deviations from theparameters of Menne’s pyr cell model in her CA3 network.Firing-pattern matching for the modeled IB�, IB+, andRS cell types was achieved by simulating distinct, relativelysmall (0.075, 0.28, and 0.70 nA, respectively) somatic ‘biascurrent’ injections. Although the use of bias currents was adeparture from Menne’s original approach, it is consistentwith the way Menschik [21] and Traub [24] suppressedspontaneous firing of their interneurons via a hyperpolar-izing ‘holding current’. Our three projection cell types wereboth intra- and interconnected to reflect recurrent con-nectivity. As a matter of programmatic convenience, weused the symbols IBw and IBs in place of IB� and IB+,respectively. The key distinction among the IBw, IBs, andRS projection cell types was chosen to be the kind ofGABAA receptor channel we assigned to each, asdetermined by their specific GABAA reversal potentials:EGABAAex

for the IBs cells and EGABAAfor the IBw and RS

neurons. A secondary consideration was the possibleimpairment of GABAB receptor function for the projectioncells, as modeled by different levels of (maximum)conductance density at these receptor sites.

Starting from Menne’s CA3 network, we decided tosubdivide her 72 pyr neurons into 36 RS projection cells,with the other 36 becoming IBw or IBs cells, in equalnumbers. This seemingly arbitrary proportioning of celltypes was loosely based on: (1) an observation by Cohen etal. [4] that 78% of the subicular pyr neurons examinedwere inhibited in response to GABAergic stimulation,while the remaining 22% were actually excited by theGABA they received; (2) a statement in Menendez de laPrida et al. [17] that a randomly sampled population ofbursting neurons (from rat subiculum) contained half ofthe IB+ type.

The work of Menendez de la Prida and discussions withother experimentalists led us to ‘collapse’ Menne’s fb and ffinterneuron models into a single FS type. Another majorpoint of departure from Menne’s treatment of her CA3-likestructure was to interconnect these FS interneurons, too.All this, of course, required us to make numerousprogrammatic modifications, in order for the FS inter-neurons to properly receive input from the randomspike

arrays, to appropriately ‘inhibit’ the three types ofprojection cells and be stimulated by them, and to enablesuitable GABA-mediated signaling among the FS cells. Wespecified the GABAA reversal potential for the FSinterneurons as EGABAAi

. Although our original ‘subicu-lum’ model was to contain 18 FS interneurons (in place ofMenne’s 9 fb and 9 ff), discussions with the experimentalistDr. Richard Miles convinced us to lower that number. Weeventually settled on 12 FS interneurons, bringing the totalnumber of subicular cells down to 84.In what follows, we present the results of parametric

studies of increasing EGABAAexvalues for the IBs cells, from

�65mV (slightly hyperpolarized to RMP) to �47.5mV(significantly depolarized to RMP). Every action potential(‘spike’) was recorded, for each of the network’s neurons,for every simulation run. An average or ‘characteristic’spike rate (CSR) was computed for each cell type, IBw,IBs, RS, and FS, during a specified 1 s. interval. In order toillustrate the fluctuations in the bin-by-bin spike rateswhose average equals the CSR, we presented some CSRgraphs as ‘‘box and whisker’’ plots.In all cases, when plotted against EGABAAex

, these CSRdata points exhibited a clear exponential growth pattern,and were fit with a function of the form y ¼ A(Bx), with x

representing EGABAAexand y the corresponding CSR. For

ease of comparison, x was chosen to be EGABAAex+60, so

that x ¼ 0 represents �60mV. With this normalization, A

is approximately the CSR at EGABAAex¼ �60mV and B

represents the exponential growth rate which best fits thedata points; we let A be replaced by R-60 and B by EGR.The ‘‘goodness of fit’’ for each case is given by itscorrelation coefficient, Corr (with Corr ¼ 1 representing aperfect fit). Using the corresponding exponential growthfunction in each case, the value of EGABAAex

for which theCSR ¼ 70Hz was computed and is denoted by E70; thevalue for which the CSR ¼ 100 is written as E100. TheGABAA reversal potentials of the IBw/RS projection cells,EGABAA

, and FS interneurons, EGABAAi, were set to �75/

�75 and �70mV, respectively, a ‘conservative’ set of‘nominal’ values for their GABAA receptor channels. Inthe Figures that follow, EGABAA

is written as EGABAA,EGABAAi

as EGABAAi, and EGABAAexas EGABAAex.

ARTICLE IN PRESS

Table 1

Key CSR-related values for the IBs and FS cells corresponding to Figs. 1 and 2, respectively, as determined by their approximating exponential growth

functions

IBs R-60 (Hz) EGR Corr E70 (mV) E100 (mV) FS R-60 (Hz) EGR Corr

20.6 1.1893 0.9914 �53.0 �50.9 40.4 1.0554 0.9243

Fig. 2. CSR as a function of increasing EGABAAexfor the FS cells.

Fig. 3. The effects of GABAB receptor impairment on the CSRs of the IBs

cells.

Table 2

Key CSR-related values for the IBs cells corresponding to Fig. 3, at

reduced levels of GABAB receptor conductance

IBs R-60 (Hz) EGR Corr E70 (mV) E100 (mV)

100% GABAB 20.6 1.1893 0.9914 �53.0 �50.9

50% GABAB 23.6 1.1824 0.9917 �53.5 �51.4

25% GABAB 27.2 1.1769 0.9935 �54.2 �52.0

0% GABAB 37.5 1.1703 0.9959 �56.0 �53.8

Fig. 4. Cellular activity patterns of a representative IBs cell, IBs11.

R. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–1625 1623

9. Results

Fig. 1 and Table 1 illustrate the effects of increasingvalues of EGABAAex

on the IBs cells’ spiking activity. It isobvious from these that the CSRs of the simulated IBs cellsfollow a definite exponential growth pattern, with arelatively high EGR growth rate. Moreover, the growthcurve shows (see also the E70 and E100 values in Table 1)that the subpopulation of simulated IBs cells can attainquite high levels of population burst-firing at physiologi-cally realizable values of EGABAAex

, relative to RMP[4,7,15,16].

Fig. 2 and Table 1 illustrate the corresponding effects ofincreasing EGABAAex

on the spiking activity of FSinterneurons. Here again, the CSRs of the FS interneurons

clearly show exponential growth with increasing EGABAAex.

It should be pointed out that data not directly presentedhere show that, while the IBs projection cells and FSinterneurons exhibit exponential growth in populationspiking, the IBw and RS projection cells demonstrateever-decreasing action potential generation.Fig. 3 and Table 2 illustrate the effects of increasing

levels of GABAB receptor impairment on the CSRs of theIBs projection cells, for increasing values of EGABAAex

.These simulation results seem to support the view thatimpaired GABAB receptor function does augment thecorresponding spiking activity brought about by increasingGABAA receptor-mediated depolarization. However,though quite common among refractory epilepsies [6,7],weakened GABAB response only seems to contribute muchto this intensified neuronal activity at high levels ofGABAA receptor activation and severely impaired GABAB

receptor function, also in agreement with our results.

ARTICLE IN PRESS

Fig. 5. Cellular activity patterns of a representative FS cell, FS1.

R. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–16251624

Fig. 4 illustrates the cellular activity patterns (viasomatic membrane potential) for one of the IBs cells,IBs11, as EGABAAex

is raised from �65 to �60, �55, and�50mV. Fig. 5 does the same for one of the FSinterneurons, FS1. Both figures are focused on thesubinterval from 0.50 to 0.75 s.

10. Conclusions

Our simulation results are based on a relatively simple,small-scale computer model of a ‘subiculum-like’ structure.However, our data seem to lend some credence to thefollowing:

(1)

When GABA is ‘excitatory’, it promotes synchronousneuronal discharges, which may lead to epileptiformevents.

(2)

Sitting in a strategic output location, the subiculumpossesses a complement of neuronal types capable ofreacting in a paroxysmal fashion to ‘excitatory’ GABA.

(3)

The key factor in this hyperactivity seems to be adepolarizing response to GABA at GABAA receptorsites on a subpopulation of the projection cells.

(4)

Weakened GABAB response only seems to contributemuch to this behavior at high levels of GABAA

receptor activation and severely impaired GABAB

receptor function.

(5) A subpopulation of excitatory cells of the subiculum

(mainly the IB+), together with the interneurons (theFS), may act as ‘‘pacemaker cells’’ in generatingepileptiform activity.

(6)

The subiculum seems to have ‘‘the right stuff’’ topropagate and perhaps even initiate epileptic dis-charges.

Acknowledgements

We would both like to express our gratitude to Dr. L.Menendez del la Prida and Dr. R. Miles for their help inunderstanding the physiology of the subiculum, Dr. R.Deisz for his expertise on the functioning of GABAA andGABAB receptors, and Dr. R. Maex for helping us learnGENESIS network simulation. Prof. Robertson wouldalso like to thank Dr. J. Martinerie for hosting him as aVisiting Researcher at the Cognitive Neuroscience andBrain Imaging Laboratory (LENA) in Paris during fall,2004.

References

[1] P. Andersen, R. Dingledine, L. Gjerstad, I.A. Langmoen, A.M. Laursen,

Two different responses of hippocampal pyramidal cells to application of

gamma-amino butyric acid, J. Physiol. 305 (1980) 279–296.

[2] M. Avoli, M. Barbarosie, A. Lucke, T. Nagao, V. Lopantsev, R.

Kohling, Synchronous GABA-mediated potentials and epileptiform

discharges in the rat limbic system in vitro, J. Neurosci. 16 (1996)

3912–3924.

[3] R. Benini, M. Avoli, Subicular networks gate hippocampal output

activity in an in vitro model of limbic seizures, J. Physiol. 566 (3)

(2005) 885–900.

[4] I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, R. Miles, On the

origin of interictal activity in human temporal lobe epilepsy in vitro,

Science 298 (2002) 1418–1421.

[5] R. Cossart, C. Bernard, Y. Ben-Ari, Multiple facets of GABAergic

neurons and synapses: multiple fates of GABA signalling in

epilepsies, Trends Neurosci. 28 (2) (2005) 108–115.

[6] R.A. Deisz, GABAB receptor-mediated effects in human and rat

neocortical neurones in vitro, Neuropharmacology 38 (1999) 1755–1766.

[7] R.A. Deisz, Cellular mechanisms of pharmacoresistance in slices

from epilepsy surgery, Novartis Found. Symp. 243 (2002) 186–206.

[8] A.T. Gulledge, G.J. Stuart, Excitatory actions of GABA in the

cortex, Neuron 37 (2003) 299–309.

[9] E. Harris, M. Stewart, Intrinsic connectivity of the rat subiculum: II.

Properties of synchronous spontaneous activity and a demonstration

of multiple generator regions, J. Comp. Neurol. 436 (2001) 506–518.

[10] C.A. Hubner, V. Stein, I. Hermans-Borgmeyer, T. Meyer, K.

Ballanyi, T.J. Jentsch, Disruption of KCC2 reveals an essential role

of K–Cl cotransport already in early synaptic inhibition, Neuron 30

(2001) 515–524.

[11] G.G. Hwa, M. Avoli, Excitatory synaptic transmission mediated by

NMDA and non-NMDA receptors in the superficial/middle layers of

the epileptogenic human neocortex maintained in vitro, Neurosci.

Lett. 143 (1992) 83–86.

[12] K. Kaila, Ionic basis of GABAA receptor channel function in the

nervous system, Prog. Neurobiol. 42 (1994) 489–537.

[13] K. Lamsa, K. Kaila, Ionic mechanisms of spontaneous GABAergic

events in rat hippocampal slices exposed to 4-aminopyridine,

J. Neurophysiol. 78 (1997) 2582–2591.

[14] K. Lamsa, T. Taira, Use-dependent shift from inhibitory to

excitatory GABAA receptor action in SP-O interneurons in the rat

hippocampal CA3 area, J. Neurophysiol. 90 (2003) 1983–1995.

[15] M. Martina, S. Royer, D. Pare, Cell-type-specific GABA responses

and chloride homeostasis in the cortex and amygdala, J. Neurophy-

siol. 86 (2001) 2887–2895.

[16] L. Menendez de la Prida, Control of bursting by local inhibition in

the rat subiculum in vitro, J. Physiol. 549 (2003) 219–230.

[17] L. Menendez de la Prida, F. Suarez, M.A. Pozo, The effect of

different morphological sampling criteria on the fraction of bursting

cells recorded in the rat subiculum in vitro, Neurosci. Lett. 322 (2002)

49–52.

pagation. Professor Ro

ARTICLE IN PRESSR. Robertson, K.M.L. Menne / Neurocomputing 70 (2007) 1619–1625 1625

[18] L. Menendez de la Prida, F. Suarez, M.A. Pozo, Electrophysiological

and morphological diversity of neurons from the rat subicular

complex in vitro, Hippocampus 13 (2003) 728–744.

[19] K.M.L. Menne, 2002. Feature extraction from realistically simulated

and recorded multisite neuronal signals. Diploma Thesis, Institute for

Signal Processing, University of Lubeck.

[20] K.M.L. Menne, T. Malina, A. Folkers, R. Maex, U.G. Hofmann,

Test of spike-sorting algorithms on the basis of simulated data,

Neurocomputing 44–46 (2002) 1119–1126.

[21] E.D. Menschik, L.H. Finkel, Neuromodulatory control of hippo-

campal function: towards a model of Alzheimer’s disease, Artif.

Intell. Med. 13 (1998) 99–121.

[22] C. Rivera, J. Voipio, J.A. Payne, E. Ruusuvuori, H. Lahtinen,

K. Lamsa, U. Pirvola, M. Saarma, K. Kaila, The K+/Cl�

cotransporter KCC2 renders GABA hyperpolarizing during neonatal

maturation, Nature 397 (1999) 215–216.

[23] C.E. Stafstrom, The role of the subiculum in epilepsy and

epileptogenesis, Epilepsy Curr. 5 (4) (2005) 121–129.

[24] R.D. Traub, R. Miles, Pyramidal cell-to-inhibitory cell spike

transduction explicable by active dendritic conductances in inhibitory

cell, J. Comp. Neurosci. 2 (1995) 291–298.

[25] R.D. Traub, A. Bibbig, A. Piechotta, A. Draguhn, D. Schmitz,

Synaptic and nonsynaptic contributions to giant IPSPs and ectopic

spikes induced by 4-aminopyridine in the hippocampus in vitro,

J. Neurophysiol. 85 (2001) 1246–1256.

[26] R.D. Traub, J.G.R. Jefferys, R. Miles, M.A. Whittington, K. Toth, A

branching dendritic model of a rodent CA3 pyramidal neurone,

J. Physiol. 481 (1) (1994) 79–95.

Richard Robertson received his undergraduate

and graduate degrees in Mathematics from the

University of California at Los Angeles. He was

Professor of Mathematics at California State

Polytechnic University, Pomona from 1969 until

his retirement in 2004. Since then he has taught

part-time at Cal Poly as Professor Emeritus.

Recently his research has been in neuroscience,

bioinformatics, and neurodynamics, especially

concerning epileptic seizure generation and pro-

bertson’s approach has mainly focused on non-

linear mathematical analyses and computer modeling/simulation of

portions of the human brain.

Kerstin Menne studied computer science with

minor subject bioinformatics at the University of

Lubeck, Germany, receiving her diploma degree

in 2002. She continued as an assistant at the

Institute for Signal Processing at the University

of Lubeck. She earned her Ph.D. by developing

new analytical techniques for intraoperative

signals that are recorded during the implantation

of deep brain stimulators. Kerstin Menne is

interested in biologically realistic modeling and

signal processing, especially via spike-detection and spike-sorting algo-

rithms. Since January 2006 she has worked as an IT consultant.