Inhibition and Epilepsy

Transcription

1 Inhibition and Epilepsy Saturday, December , 12:02 PM Inhibition and Epilepsy Citation: Avoli, M (2004) History of Neuroscience: Inhibition and Epilepsy, IBRO History of Neuroscience [ Accessed: date Massimo Avoli Recurrence of paroxysmal neurological and/or behavioral manifestations, commonly termed seizures, is the hallmark of epilepsy. Epileptic seizures are generally considered hyperexcitable phenomena resulting from a chronic imbalance between excitatory and inhibitory events. Hence, since GABA is the major inhibitory transmitter in the CNS, impairment of GABA function should lead to seizures, while enhancing its efficacy may exert an anticonvulsant action. Reviews of the role played by GABA in seizure generation and epileptogenesis have appeared in the last few years (3, 23). Today, it is well established that postsynaptic activation of GABA A receptors mediates fast inhibition caused by a Cl - conductance, while GABAB receptor activation leads to a relatively slow form of inhibition due to a G-protein-linked, increase in K + conductance (Figure 1A). In both cases GABA acts by increasing the membrane conductance for ions that have an equilibrium potential near or more negative than the resting membrane potential. In this way neurons hyperpolarize, thus preventing action potential firing. GABAB (and perhaps GABAA ) receptors are also found on the nerve endings of cortical neurons where they inhibit transmitter release by reducing Ca2 + entry. When they are localized at excitatory terminals, activation of GABA B receptors inhibits glutamate release and thus the overall effect is a decrease in excitation (Figure 1B). However, when they are situated at inhibitory terminals (these receptors are also known as autoreceptors) their activation causes a decreased release of GABA (Figure 1C), which may in turn result in neuronal network excitation. 1/8

2 Figure 1: A: Cortical GABA- mediated postsynaptic potentials; monosynaptic inhibitory re sponse recorded with a K- acetate- filled, intracellular electrode in a human cortical neuron in the presence of ionotropic excitatory amino acid receptor antagonists (Control). The arrows point at the fast and slow hyperpolarizations mediated by the activation of type A and type B GABA receptors, respectively. This conclusion is derived from the pharmacological analysis performed with the GABA A receptor antagonist bicuculline methiodide (BMI) and the GABA B receptor antagonist P3- aminopropyl, P- diethoxymethyl phosphoric acid (CGP 35348). B & C: GABA- mediated presynaptic inhibition; in B, activation of the GABA B receptors following application of baclofen leads to blockade of both hyperpolarizing and depolarizing spontaneous postsynaptic potentials recorded with a K- acetate/qx314- filled electrode from a CA3 pyramidal neuron treated with 4- aminopyridine. This effect is reversed by applying the GABA B receptor antagonist CGP In C, paired- pulse depression of the monosynaptic inhibitory responses recorded with a KCl/QX314- filled electrode from a bursting neuron in the rat subicular cortex under control (i.e. during application of ionotropic amino acid receptor antagonist) and after bath application of the GABA B receptor antagonist CGP Paired pulse depression is not seen under the latter conditions thus indicating the participation of GABAB receptors in the reduction of the amplitude of the response induced by the second stimulus. From Avoli The oldest demonstration of a relation between GABA and seizures rests on the occurrence of convulsions in infants fed with a formula accidentally made deficient in pyridoxine during processing (17). Pyridoxine, known also as vitamin B6, is the coenzyme for the formation of GABA from glutamic acid by means of the enzyme glutamic acid decarboxylase (GAD). Several studies have later confirmed that substances capable of interfering with GABA synthesis, release or postsynaptic effects cause convulsions in vivo or epileptiform synchronization in vitro. Moreover, weakening and/or blockade of GABA- mediated inhibition have been reported to occur shortly before the onset of seizure activity in several animal models of epileptiform discharge both in vivo and in vitro (3). The relevance of these data within the context of chronic epileptic disorders remains debatable. In fact most of this evidence has been obtained in normal brains subjected to 'acute' manipulations. Some studies have shown that particular types of cortical (neocortex and hippocampus) 2/8

3 GABAergic cells are not damaged in animal models of mesial temporal lobe epilepsy and in epileptic patients (14). However, other authors have observed a loss of GABAergic neurons and axon terminals in human sclerotic epileptic hippocampus, being basket cells and chandelier cells two of the interneuronal types affected (1). It has been also reported that decreased inhibitory control within the epileptic limbic system results from the functional disconnection of interneurons from excitatory inputs (11, 27, 29). Functional changes in inhibitory mechanisms in patients with mesial temporal lobe epilepsy may also relate to deficits in GABA transporter function (30) or alterations in GABA A receptor subunit composition (13, 18, 24). Indeed, GABA A receptor function in the dentate gyrus of epileptic animals is altered by Zn 2 + (6, 7). This represents an interesting mechanism as the reorganized mossy fibers in the dentate gyrus contain this metal. Emerging evidence indicates that GABA may promote epileptiform synchronization. For instance, GABA receptor- mediated inhibition can facilitate the thalamocortical processes leading to the occurrence of generalized spike and wave discharges that occur during absence seizures in primary generalized epilepsy. The synchronous activity generated by thalamocortical relay cells is regulated by the inhibitory inputs that originate from neurons of the thalamic nucleus reticularis (9, 15). These inputs elicit both fast GABA A and slow GABA B receptor-mediated hyperpolarizing IPSPs that cause rebound action potential bursts in thalamocortical relay neurons, thanks to deinactivation of a T-type Ca 2+ current. The thalamocortical volleys in turn excite cortical cells that re- excite nucleus reticularis neurons via corticothalamic connections. Hence, hypersynchrony within the thalamocorticothalamic loop can be insured through GABA receptor- mediated mechanisms that re- configure the thalamocortical network operation into patterns of activity characteristic of spike and wave discharge. Data obtained from slices obtained from beta 3 knockout mice has confirmed that the excitability of nucleus reticularis neurons modulates thalamocortical oscillatory synchrony (16). Moreover, intraperitoneal injection of GABA mimetics induces a dose- dependent increase in the duration of the spike and wave discharges in several genetic models of absence seizures (10, 12, 21). Early studies performed in the model of feline generalized penicillin epilepsy have also indicated that GABA A receptor-mediated potentials are still operant in neocortical cells that participate in spike and wave discharges (5). GABA A receptor-activated channels can also depolarize cortical neurons. Indeed, GABA A -mediated depolarizations can be recorded following intense synaptic activation or during application of 4- aminopyridine, and they often result from the activation of GABA A receptors located on dendrites (Figure 2). This might imply that [Cl-] i in the dendrites of cortical neurons is much higher than in the soma, where hyperpolarizations are recorded. However, GABA A receptor-mediated depolarizations also occur because GABA A receptor-activated channels can become permeable to HCO3-, an anion with equilibrium potential more positive than Cl - (19, 28). GABA A receptormediated depolarizing postsynaptic responses are also contributed by an increase in [K+]o that may be largely dependent on the HCO 3 - conductance (4). Moreover, intense synaptic activation of GABA A receptors in the adult hippocampus leads to Ca 2+ neuronal uptake through the activation of voltage-gated Ca 2+ channels by the HCO 3 - -dependent depolarization (2). GABA A receptormediated depolarizations have been recorded in the guinea- pig hippocampus from inhibitory interneurons of the dentate hilus where they contribute to interneuron synchronization (22).

4 Figure 2: GABA- mediated long- lasting depolarizations (asterisks) generated by a hippocampal neuron during application of low concentrations of the K + channel blocker 4-aminopyridine (Control) in response to stratum (s.) radiatum stimulation or spontaneously, but not following alvear stimuli. Note that the long-lasting depolarizations are preceded by an early (GABA A - receptor-mediated) hyperpolarizing potential and followed by a long-lasting (GABA B -receptormediated) hyperpolarization. Local application of bicuculline methiodide (BMI) to the apical dendrites causes a selective depression of both evoked and spontaneous long- lasting depolarizations whereas the antidromic recurrent IPSP is still recorded. From Avoli Activation of GABA A receptors leading to elevation in [K + ] o can paradoxically initiate ictal activity in the CA3 area of the young rat hippocampus (Figure 3A) and in the adult rat or mouse entorhinal cortex (Figure 3B).

5 Figure 3: GABA- mediated synchronization leads to the onset of epileptiform discharge during application of 4- aminopyridine. A: Simultaneous field potential (Field) and intracellular (Intra) recordings performed in the CA3 area of a 22-day-old rat. The onset of the ictal discharge is illustrated at an expanded time base to show details of the initial GABA- mediated potential and subsequent ictal discharge. B: Simultaneous field potential (Field) and [K + ] o recordings performed in the adult rat entorhinal cortex show the occurrence of spontaneous negative potentials that are associated with increases in [K + ] o (a). In b, an ictal discharge is initiated by a negative-going potential. Note that [K + ] o increases during this negative potential (arrow) and attains values that are larger than those associated with the isolated negative- going potentials. From Avoli Hence, GABA receptor- mediated synchronization may serve as a powerful implement for the initiation of epileptiform activity. It is well known that increasing [K + ] o induces a positive shift of GABA- mediated postsynaptic inhibition, depolarizes neurons and disinhibits excitatory postsynaptic interaction. The facilitatory effects of GABA receptor mechanisms in implementing ictal discharges is supported by the ability of pharmacological procedures that interfere with GABAergic transmission (e.g. activation of µ- opioid receptors causing interneuron hyperpolarization and thus a decreased GABA release) to abolish GABA- mediated synchronous potentials along with the ictallike discharges (Figure 4). 5/8

6 Figure 4: Pharmacological demonstration of the role played by the synchronus GABA- mediated potential in the initiation of ictal discharges in juvenile hippocampus (A) and in the adult entorhinal cortex (B). A: Activation of µ-opioid receptors by DAGO ([D-Ala 2,N-Me-Phe 4,Gly-ol 5 ]enkephalin), which abolishes GABA release from interneuron terminals, blocks both GABA- mediated field potentials and ictal discharges recorded with field potential and [K +] o recordings during application of 4- aminopyridine in the CA3 subfiled of a hippocampal slice obtained from a young rat hippocampus. From ref 63. B: Similar effects are seen during DAGO application to a combined hippocampal- entorhinal cortex slice that was also treated with 4- aminopyridine. In this experiment field potential recordings were obtained from the entorhinal cortex (EC) and the CA3 subfield. Note that interictal discharges continue to occur in both experiments. From Avoli Synchronous GABA A receptor-mediated depolarizing potentials are also generated spontaneously by hippocampal neurons early in life (8). It has been proposed that these depolarizing events represent a key element for controlling several Ca 2+ -dependent developmental phenomena that include cell proliferation, migration and targeting (20, 26). The molecular and cellular mechanisms responsible for the generation of these GABA A -mediated depolarizations in each of these specific conditions remain unclear. However, recent findings indicate that the ontogenetic changes in GABA A receptor-mediated responses from depolarizing to hyperpolarizing is coupled to a developmental expression in neurons of a Cl - -extruding K + /Cl - co-transporter, that may also represent the main promoter of fast hyperpolarizing postsynaptic inhibition in the mature brain (25). Over fifty years of research on GABA functions have made possible to identify several actions that are mediated by this neurotransmitter. Indeed, when expressed in the complexity of the brain function, the role of GABA receptors goes far beyond the original inhibitory role described in early studies. As a result we face today scenarios that are at times in antithesis with the simple view that seizures stem from a decrease in GABA receptor- mediated inhibition. Nonetheless, one must recognize that epileptiform discharges, whether caused by a mechanism related to GABA function or not, can be controlled by GABA strategies that include the use of traditional pharmacological approaches that increase the efficacy of GABA receptor- mediated mechanisms. Massimo Avoli Montreal Neurological Institute and Departments of Neurology & Neurosurgery and Physiology 6/8

7 McGill University Montreal, Que., H3A 2B4, Canada Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma "La Sapienza", Roma, Italy IRCCS Neuromed, 86077, Pozzilli (IS) Italy massimo.avoli@mcgill.ca References 1. Arellano JI, Muñoz A, Ballesteros- Yáñez I, Sola RG, DeFelipe J. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain 2004; 127: Autere AM, Lamsa K, Kaila K, Taira T. Synaptic activation of GABA A receptors induces neuronal uptake of Ca 2+ in adult hippocampal slices. J Neurophysiol 1999; 81: Avoli M. Epilepsy. Chapter in GABA in The Nervous System: TheView at Fifty Years. Martin DL, Olsen RW (Eds). Lippincott, Williams & Wilkins, Philadelphia: , Avoli M, D'antuono M, Louvel J, Kohling R, Biagini G, Pumain R, D'arcangelo G, Tancredi V. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system. Progress in Neurobiology 2002; 68: Avoli M, Gloor P, Kostopoulos G. Focal and generalized epileptiform activity in the cortex: in search of differences in synaptic mechanisms, ionic movements, and long- lasting changes in neuronal excitability. Chapter in Generalized Epilepsy: Neurobiological Approaches. Avoli M, Gloor P, Kostopoulos G, Naquet R (Eds). Birkhäuser Boston, Basel and Berlin: , Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in single cell GABA A receptor subunit expression and function in temporal lobe epilepsy. Nat Med 1998; 4: Buhl EH, Otis TS, Mody I. Zinc-induced collapse of augmented GABAergic inhibition by GABA in a temporal lobe epilepsy model. Science 1996; 271: Cherubini E, Gaiarsa JL, Ben- Ari Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 1991; 14: Crunelli V, Leresche N. A role for GABA B receptors in excitation and inhibition of thalamocortical cells. Trends Neurosci 1991; 14: Danober L, Deransart C, Deapulis A, Vergnes M, Marescaux C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Progr Neurobiol 1998; 55: Empson RM, Jefferys JG. Synaptic inhibition in primary and secondary chronic epileptic foci induced by intrahippocampal tetanus toxin in the rat. J Physiol (Lond) 1993; 465: Hosford DA, Wang Y, Cao Z. Differential effects mediated by GABAA receptors in thalamic nuclei in lh/lh model of absence seizures. Epilepsy Res 1997; 27: Houser CR, Esclapez M. Downregulation of the alpha5 subunit of the GABA(A) receptor in the pilocarpine model of temporal lobe epilepsy. Hippocampus 2003; 13: Houser CR. Neuronal loss and synaptic reorganization in temporal lobe epilepsy. Chapter in Jasper's Basic Mechanisms of Epilepsies, Third Edition: Advances in Neurology, Vol. 79. Delgado- Escuetta AV, Wilson WA, Olsen RW, Porter RJ (Eds). Lippincott Williams & Wilkins, Philadelphia: , Huguenard JR, McCormick DA, Coulter D. Thalamocortical interactions. Chapter in The Cortical Neuron. Gutnick MJ, Mody I (Eds). Oxford: Oxford University Press, New York: , Huntsman MM, Porcello DM, Homanics GE, DeLorey TM, Huguenard JR. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 1999; 283: Jasper HH. The Saga of K.A.C. Elliott and GABA. Neurochem Res 1984; 9: Kamphuis W, DeRijk TC, Lopes da Silva FH. Expression of GABA A receptor subunit mrnas in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. Mol Brain Res 1995; 31: Lamsa K, Kaila K. Ionic mechanisms of spontaneous GABAergic events in rat hippocampal slices exposed to 4- aminopyridine. J Neurophysiol 1997;78: Lo Turco J, Owens D, Heath M, Davis M, Kriegstein A. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 1995; 15: Meldrum B, Horton R. Effects of the bicyclic GABA agonist THIP on myoclonic and seizure 7/8

8 12/15/12 responses in mice and baboons with reflex epilepsy. Eur J Pharmacol 1980; 61 : Michelson HB, Wong RKS. Excitatory synaptic responses mediated by GABA A receptors in the hippocampus. Science 1991; 253: Olsen RW, Avoli M. GABA and epileptogenesis. Epilepsia 1997; 38: Rice A, Rafiq A, Shapiro SM, Jakoi ER, Coulter DA, De Lorenzo RJ. Long-lasting reduction of inhibitory function and gamma- aminobutyric acid type A receptor subunit mrna expression in a model of temporal lobe epilepsy. Proc Natl Acad Sci USA 1996; 93: Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K. The K + /Cl - co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 1999; 397: Serafini R, Valeyev AY, Barker JL, Poulter MO. Depolarizing GABA- activated Cl- channels in embryonic rat spinal and olfactory bulb cells. J Physiol (Lond) 1995; 488: Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experi mental epilepsy. Science 1987; 235: Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995; 269: Williams S, Vachon P, Lacaille JC. Monosynaptic GABA- mediated inhibitory postsynaptic potentials in CA1 pyramidal of hyperexcitable hippocampal slices from kainic acid- treated rats. Neuroscience 1993; 52: Williamson A, Telfeian AE, Spencer DD. Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis. J Neurophysiol 1995; 74: /8