J Physiol 588.1 (2010) pp 17–18 17

CL IN ICAL PERSPECT IVES

How much inhibition in anepileptiform burst?

Ivan Pavlov and Dimitri M. KullmannUCL Institute of Neurology, Queen SquareHouse, Queen Square, London WC1N 3BG,UK

Email: d.kullmann@ion.ucl.ac.uk

GABAA receptor-mediated signalling andlocalisation-related epilepsy have a longand tortuous relationship. Since GABAA

receptors mediate fast inhibition in thecortex the simple view is that theyprevent seizures. In keeping with this,loss-of-function mutations of GABAA

receptor subunits are associated with rarefamilial forms of epilepsy. Furthermore,experimental epilepsy in rodents has beenshown to be associated with loss of inter-neurons that release GABA in brain regionsinvolved in focal seizure generation suchas the hippocampal formation. Althoughneuronal loss is not restricted to inter-neurons, some studies have reported adecrease in the number and strengthof GABAergic synapses on survivingprincipal (excitatory) neurons. And indeed,potentiating GABAergic neurotransmissionwith barbiturates, benzodiazepines orGABA uptake blockers such as tiagabine,is a highly effective anti-epileptic strategy.But these drugs do not always work,and some forms of epilepsy arising fromcortical foci can be stubbornly resistant topharmacotherapy. Why is this?

Under normal conditions GABAergicneurotransmission not only inhibitsprincipal neurons but, helped by thefast kinetics of some interneurons andGABAergic synapses, also provides amechanism to synchronise their firing.This feature of GABAergic signallingdepends in particular on ‘perisomatic’synapses made on the cell bodies andaxon initial segments of principal cells.Recent studies on tissue from patientswith intractable epilepsy (Wittner et al.2005) and rodents with experimentalepilepsy (Cossart et al. 2001) show that,unlike ‘dendritic’ inhibition, perisomaticGABAergic inputs can be preserved oreven enhanced relative to control tissue.This phenomenon might be compensatory,

counteracting an increased level of activityin the pathological network. However, itmay also shift the balance between thetwo effects of GABAergic transmission:away from dendritic inhibition (which isgenerally thought to counteract integrationof excitatory inputs) towards perisomaticinhibition, which could lead to excessivesynchronization. This, together with anincreased propensity of pyramidal neuronsto fire in bursts, may contribute to abnormalnetwork dynamics. A further twist is thatGABA could even treacherously swapsides because of a change in intracellularchloride ion concentration, and turn intoan excitatory neurotransmitter (Cohenet al. 2002).

Against this background, a qualitativedescription of how GABAergic signallingchanges in epilepsy is insufficient: what weneed is a quantitative understanding of howmany interneurons contribute to generateperisomatic and dendritic currents, and ofthe relative amplitudes and kinetics of thedifferent types of GABAA receptor-mediatedsignals. In a recent issue of The Journal ofPhysiology Marchionni & Maccaferri (2009)take the first step towards such a quantitativedescription. They take advantage of thefact that epileptiform network activity doesnot require the physical loss of GABAergicsynapses per se: with appropriate ionic orpharmacological manipulations both inter-ictal and ictal discharges can be inducedin brain tissue from non-epileptic animals.The authors compare the amplitudes ofmonosynaptic GABAergic signals elicitedin pyramidal neurons by action potentialsin individual interneurons before andafter switching a hippocampal slice to amagnesium-free perfusion solution withincreased potassium concentration inorder to induce spontaneous bursts ofactivity. Using the results from previousmorphological studies, they estimate thenumber of GABAergic neurons recruitedby such bursts. It turns out that mostif not all available perisomatic-targetinginterneurons fire. They extend this tosome technically challenging simultaneousrecordings from the cell bodies anddendrites of individual pyramidal neurons,in order to ask whether the almost universalinvolvement of interneurons is restrictedto those that are specialised to project

to the perisomatic region. Although whathappens in distal dendrites remains to bedetermined, it turns out that bursts ofinhibition in proximal dendrites behave verysimilarly to those detected at the soma.

What are the implications of these findingsfor epilepsy? Although near-universalrecruitment of perisomatic-projectinginterneurons may predispose the networkto hypersynchronous behaviour, anotherpossibility is that such massive activationacts to retard the spread of epileptiformactivity. Such a role for feed-forwardinhibition as a final barrier to thepropagation of excessive activity has beendemonstrated in layer 5 of the neocortexin a similar in vitro model (Trevelyanet al. 2007). Indeed, the intermittent burstdischarges studied by Marchionni andMaccaferri may be less a model of epilepticseizures than of interictal dischargesas occur in patients with epilepsy, andwhich have been proposed to have ananti-ictogenic role (de Curtis & Avanzini,2001). Clearly, much work remains to bedone to understand the roles of differentforms of fast GABAergic signalling in ‘real’epilepsy, not least by examining other invitro manipulations to trigger spontaneousactivity, by studying tissue from rodentsat distinct developmental stages wherechloride homeostasis may be quitedifferent, and eventually by comparingto tissue from animals with establishedepilepsy. The quantitative approach takenby Marchionni and Maccaferri showsthat a synthesis of anatomical, electro-physiological and pharmacological toolsneeds to be brought to bear on this difficultproblem.

References

Cohen I, Navarro V, Clemenceau S, Baulac M &Miles R (2002). On the origin of interictalactivity in human temporal lobe epilepsy invitro. Science 298, 1418–1421.

Cossart R, Dinocourt C, Hirsch JC,Merchan-Perez A, De Felipe J, Ben-Ari Y,Esclapez M & Bernard C (2001). Dendriticbut not somatic GABAergic inhibition isdecreased in experimental epilepsy. NatNeurosci 4, 52–62.

de Curtis M & Avanzini G (2001). Interictalspikes in focal epileptogenesis. Prog Neurobiol63, 541–567.

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society DOI: 10.1113/jphysiol.2009.184150

18 Clinical Perspectives J Physiol 588.1

Marchionni I & Maccaferri G (2009).Quantitative dynamics and spatial profile ofperisomatic GABAergic input duringepileptiform synchronization in the CA1hippocampus. J Physiol 587, 5691–5708.

Trevelyan AJ, Sussillo D & Yuste R (2007).Feedforward inhibition contributes to thecontrol of epileptiform propagation speed. JNeurosci 27, 3383–3387.

Wittner L, Eross L, Czirjak S, Halasz P, FreundTF & Magloczky Z (2005). Surviving CA1pyramidal cells receive intact perisomaticinhibitory input in the human epileptichippocampus. Brain 128, 138–152.

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society