Abstract
Identifying the role of GABA neurons in the development of an epileptic state has been particularly difficult in acquired epilepsy, in part because of the multiple changes that occur in such conditions. Although once questioned, there is now considerable evidence for loss of GABA neurons in multiple brain regions in models of acquired epilepsy. This loss can affect several cell types, including both somatostatin- and parvalbumin-expressing interneurons, and the cell type that is most severely affected can vary among brain regions and models. Because of the diversity of GABA neurons in the hippocampus and cerebral cortex, resulting functional deficits are unlikely to be compensated fully by remaining GABA neurons of other subtypes. The fundamental importance of GABA neuron loss in epilepsy is supported by findings in genetic mouse models in which GABA neurons appear to be decreased relatively selectively, and increased seizure susceptibility and spontaneous seizures develop. Alterations in remaining GABA neurons also occur in acquired epilepsy. These include alterations in inputs or receptors that could impair function, as well as morphological reorganization of GABAergic axons and their synaptic connections. Such axonal sprouting could be compensatory if normal circuits are reestablished, but the creation of aberrant circuitry could contribute to an epileptic condition. The functional effects of GABA neuron alterations thus may include not only reductions in GABAergic inhibition but also excessive neuronal synchrony and, potentially, depolarizing GABAergic influences. The combination of GABA neuron loss and alterations in remaining GABA neurons provides likely, though still unproven, substrates for the epileptic state.
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Abbreviations
- CCK:
-
Cholecystokinin
- eGFP:
-
Enhanced green fluorescent protein
- eYFP:
-
Enhanced yellow fluorescent protein
- GABA:
-
Gamma aminobutyric acid
- GAD:
-
Glutamic acid decarboxylase
- NPY:
-
Neuropeptide Y
- PV:
-
Parvalbumin
- SOM:
-
Somatostatin
- s. oriens:
-
Stratum oriens
- TLE:
-
Temporal lobe epilepsy
- uPAR :
-
Urokinase plasminogen activator receptor
References
Andre V, Marescaux C, Nehlig A, Fritschy JM (2001) Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus 11:452–468
Andrioli A, Alonso-Nanclares L, Arellano JI, DeFelipe J (2007) Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus. Neuroscience 149:131–143
Armstrong C, Soltesz I (2012) Basket cell dichotomy in microcircuit function. J Physiol 590:683–694
Bausch SB (2005) Axonal sprouting of GABAergic interneurons in temporal lobe epilepsy. Epilepsy Behav 7:390–400
Bernard C, Esclapez M, Hirsch JC, Ben-Ari Y (1998) Interneurons are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res 32:93–103
Boulland JL, Ferhat L, Tallak Solbu T, Ferrand N, Chaudhry FA, Storm-Mathisen J, Esclapez M (2007) Changes in vesicular transporters for gamma-aminobutyric acid and glutamate reveal vulnerability and reorganization of hippocampal neurons following pilocarpine-induced seizures. J Comp Neurol 503:466–485
Buckmaster PS, Dudek FE (1997) Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comp Neurol 385:385–404
Catterall WA, Kalume F, Oakley JC (2010) NaV1.1 channels and epilepsy. J Physiol 588:1849–1859
Cavalheiro EA, Fernandes MJ, Turski L, Naffah-Mazzacoratti MG (1994) Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus. Epilepsia 35:1–11
Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, Baraban SC, Rubenstein JL (2005) Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci 8:1059–1068
Cossart R, Dinocourt C, Hirsch JC, Merchan-Perez A, DeFelipe J, Ben-Ari Y, Esclapez M, Bernard C (2001) Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat Neurosci 4:52–62
Davenport CJ, Brown WJ, Babb TL (1990) Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat. Exp Neurol 109:180–190
DeFelipe J (1999) Chandelier cells and epilepsy. Brain 122:1807–1822
de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD (1989) Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 495:387–395
Dinocourt C, Petanjek Z, Freund TF, Ben-Ari Y, Esclapez M (2003) Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine-induced seizures. J Comp Neurol 459:407–425
Drexel M, Preidt AP, Kirchmair E, Sperk G (2011) Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures. Neuroscience 189:316–329
Dutton SB, Makinson CD, Papale LA, Shankar A, Balakrishnan B, Nakazawa K, Escayg A (2012) Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiol Dis 49:211–220
Esclapez M, Hirsch JC, Khazipov R, Ben-Ari Y, Bernard C (1997) Operative GABAergic inhibition in the hippocampal CA1 pyramidal neurons in experimental epilepsy. Proc Natl Acad Sci U S A 94:12151–12156
Esclapez M, Houser CR (1999) Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy. J Comp Neurol 412:488–505
Feldblum S, Ackermann RF, Tobin AJ (1990) Long-term increase of glutamate decarboxylase mRNA in a rat model of temporal lobe epilepsy. Neuron 5:361–371
Ferando I, Mody I (2012) GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies. Epilepsia 53(Suppl 9):89–101
Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470
Freund TF, Katona I (2007) Perisomatic inhibition. Neuron 56:33–42
Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I (2007) A new naturally occurring GABAA receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci 10:40–48
Gorter JA, van Vliet EA, Aronica E, Lopes da Silva FH (2001) Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons. Eur J Neurosci 13:657–669
Halabisky B, Parada I, Buckmaster PS, Prince DA (2010) Excitatory input onto hilar somatostatin interneurons is increased in a chronic model of epilepsy. J Neurophysiol 104:2214–2223
Houser CR, Esclapez M (1996) Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures. Epilepsy Res 26:207–218
Hunt RF, Girskis KM, Rubenstein JL, Alvarez-Buylla A, Baraban SC (2013) GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci 16:692–697
Kobayashi M, Buckmaster PS (2003) Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci 23:2440–2452
Kumar SS, Buckmaster PS (2006) Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 26:4613–4623
Lau D, Vega-Saenz de Miera EC, Contreras D, Ozaita A, Harvey M, Chow A, Noebels JL, Paylor R, Morgan JI, Leonard CS, Rudy B (2000) Impaired fast-spiking, suppressed cortical inhibition, and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins. J Neurosci 20:9071–9085
Lowenstein DH, Thomas MJ, Smith DH, McIntosh TK (1992) Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 12:4846–4853
Marksteiner J, Sperk G (1988) Concomitant increase of somatostatin, neuropeptide Y and glutamate decarboxylase in the frontal cortex of rats with decreased seizure threshold. Neuroscience 26:379–385
Martin MS, Dutt K, Papale LA, Dube CM, Dutton SB, de Haan G, Shankar A, Tufik S, Meisler MH, Baram TZ, Goldin AL, Escayg A (2010) Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. J Biol Chem 285:9823–9834
Mathern GW, Babb TL, Pretorius JK, Leite JP (1995) Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. J Neurosci 15:3990–4004
Morin F, Beaulieu C, Lacaille J–C (1998) Selective loss of GABA neurons in area CA1 of the rat hippocampus after intraventricular kainate. Epilepsy Res 32:363–369
Obenaus A, Esclapez M, Houser CR (1993) Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J Neurosci 13:4470–4485
Peng Z, Huang CS, Stell BM, Mody I, Houser CR (2004) Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci 24:8629–8639
Peng Z, Zhang N, Wei W, Huang CS, Cetina Y, Otis TS, Houser CR (2013) A reorganized GABAergic circuit in a model of epilepsy: evidence from optogenetic labeling and stimulation of somatostatin interneurons. J Neurosci 33:14392–14405
Powell EM, Campbell DB, Stanwood GD, Davis C, Noebels JL, Levitt P (2003) Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J Neurosci 23:622–631
Ribak CE (1985) Axon terminals of GABAergic chandelier cells are lost at epileptic foci. Brain Res 326:251–260
Robbins RJ, Brines ML, Kim JH, Adrian T, de Lanerolle NC, Welsh S, Spencer DD (1991) A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy. Ann Neurol 29:325–332
Rossignol E, Kruglikov I, van den Maagdenberg AM, Rudy B, Fishell G (2013) Cav2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann Neurol 74:209–222
Schwarzer C, Williamson JM, Lothman EW, Vezzani A, Sperk G (1995) Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy. Neuroscience 69:831–845
Sloviter RS (1987) Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235:73–76
Sloviter RS (1991) Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1:41–66
Sloviter RS, Zappone CA, Harvey BD, Bumanglag AV, Bender RA, Frotscher M (2003) “Dormant basket cell” hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat. J Comp Neurol 459:44–76
Sundstrom LE, Brana C, Gatherer M, Mepham J, Rougier A (2001) Somatostatin- and neuropeptide Y-synthesizing neurones in the fascia dentata of humans with temporal lobe epilepsy. Brain 124:688–697
Swartz BE, Houser CR, Tomiyasu U, Walsh GO, DeSalles A, Rich JR, Delgado-Escueta A (2006) Hippocampal cell loss in posttraumatic human epilepsy. Epilepsia 47:1373–1382
Thind KK, Yamawaki R, Phanwar I, Zhang G, Wen X, Buckmaster PS (2010) Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol 518:647–667
Wyeth MS, Zhang N, Mody I, Houser CR (2010) Selective reduction of cholecystokinin-positive basket cell innervation in a model of temporal lobe epilepsy. J Neurosci 30:8993–9006
Yu J, Proddutur A, Elgammal FS, Ito T, Santhakumar V (2013) Status epilepticus enhances tonic GABA currents and depolarizes GABA reversal potential in dentate fast-spiking basket cells. J Neurophysiol 109:1746–1763
Zhang W, Buckmaster PS (2009) Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy. J Neurosci 29:7846–7856
Zhang W, Yamawaki R, Wen X, Uhl J, Diaz J, Prince DA, Buckmaster PS (2009) Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synapses with granule cells in a mouse model of temporal lobe epilepsy. J Neurosci 29:14247–14256
Acknowledgments
I would like to express my deep gratitude to Phil Schwartzkroin for his generous spirit and support over many years; his insightful and thought-provoking questions that have stimulated and enhanced basic science research in the epilepsy field; and his deep commitment and service to the entire epilepsy community which will continue in many forms.
Other Acknowledgements
This work was supported by National Institutes of Health Grant NS075245 and Veterans Affairs Medical Research Funds. I gratefully acknowledge the members of my laboratory, past and present, for their superb work and strong dedication to our studies of GABA neurons and epilepsy.
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Houser, C.R. (2014). Do Structural Changes in GABA Neurons Give Rise to the Epileptic State?. In: Scharfman, H., Buckmaster, P. (eds) Issues in Clinical Epileptology: A View from the Bench. Advances in Experimental Medicine and Biology, vol 813. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8914-1_12
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