Clinical and experimental evidence indicates that inflammatory processes contribute to the pathophysiology of epilepsy, but underlying mechanisms remain mostly unknown. Using immunohistochemistry for CD45 (common leukocyte antigen) and CD3 (T-lymphocytes), we show here microglial activation and infiltration of leukocytes in sclerotic tissue from patients with mesial temporal lobe epilepsy (TLE), as well as in a model of TLE (intrahippocampal kainic acid injection), characterized by spontaneous, nonconvulsive focal seizures. Using specific markers of lymphocytes, microglia, macrophages, and neutrophils in kainate-treated mice, we investigated with pharmacological and genetic approaches the contribution of innate and adaptive immunity to kainate-induced inflammation and neurodegeneration. Furthermore, we used EEG analysis in mutant mice lacking specific subsets of lymphocytes to explore the significance of inflammatory processes for epileptogenesis. Blood-brain barrier disruption and neurodegeneration in the kainate-lesioned hippocampus were accompanied by sustained ICAM-1 upregulation, microglial cell activation, and infiltration of CD3 ϩ T-cells. Moreover, macrophage infiltration was observed, selectively in the dentate gyrus where prominent granule cell dispersion was evident. Unexpectedly, depletion of peripheral macrophages by systemic clodronate liposome administration affected granule cell survival. Neurodegeneration was aggravated in kainate-lesioned mice lacking T-and B-cells (RAG1-knock-out), because of delayed invasion by Gr-1 ϩ neutrophils. Most strikingly, these mutant mice exhibited early onset of spontaneous recurrent seizures, suggesting a strong impact of immunemediated responses on network excitability. Together, the concerted action of adaptive and innate immunity triggered locally by intrahippocampal kainate injection contributes seizure-suppressant and neuroprotective effects, shedding new light on neuroimmune interactions in temporal lobe epilepsy.
Pregnancy is associated with changes in mood and anxiety level as well as with marked hormonal fluctuations. Increases in the brain concentrations of neuroactive steroids during pregnancy in rats are accompanied by changes in expression of subunits of the GABA type A receptor (GABA A -R) in the brain. Granule cells of the dentate gyrus (DGGCs) exhibit two components of inhibitory GABAergic transmission: a phasic component mediated by synaptic GABA A -Rs, and a tonic component mediated by extrasynaptic GABA A -Rs. Recordings of GABAergic currents were obtained from hippocampal slices prepared from rats in estrus, at pregnancy day 15 (P15) or P19, or at 2 d after delivery. Exogenous GABA or 3␣,5␣-THP induced an increase in tonic current in DGGCs that was significantly greater at P19 than in estrus. Neither tonic nor phasic currents were affected by pregnancy in CA1 pyramidal cells. Immunohistochemical analysis revealed a marked increase in the abundance of the ␦ subunit of the GABA A -R and a concomitant decrease in that of the ␥ 2 subunit in the hippocampus at P19. Expression of the ␣ 4 subunit did not change during pregnancy but was increased 2 d after delivery. Treatment of rats from P12 to P18 with the 5␣-reductase inhibitor finasteride prevented the changes in tonic current and in ␦ and ␥ 2 subunit expression normally apparent at P19. These data suggest that the number of extrasynaptic GABA A -Rs is increased in DGGCs during late pregnancy as a consequence of the associated marked fluctuations in the brain levels of neuroactive steroids.
Previously we have demonstrated that social isolation of rats reduces both the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG), and potentiates the positive effects of acute ethanol administration on the concentrations of this neurosteroid. We now show that the ethanol-induced increase in 3a,5a-TH PROG is more pronounced in the brain than in the plasma of isolated rats. The ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect is prevented by treatment with finasteride. Social isolation modified the effects of ethanol on the amounts of steroidogenic regulatory protein mRNA and protein in the brain. Moreover, ethanol increased the amplitude of GABA A receptor-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurones with greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed rats, an effect inhibited by finasteride. The amounts of the a 4 and d subunits of the GABA A receptor in the hippocampus were increased in isolated rats as were GABA A receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. These results suggest that social isolation results in changes in GABA A receptor expression in the brain, and in an enhancement of the stimulatory effect of ethanol on brain steroidogenesis, GABA A receptor function and associated behaviour. Social isolation of rats after weaning results in a decrease in the brain and plasma concentrations of neuroactive steroids such as 3a-hydroxy-5a-pregnan-20-one (allopregnanolone, 3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone . The molecular mechanisms that underlie this effect remain unclear. However, consistent with the hypothesis that ethanol (EtOH) activates the hypothalamicpituitary-adrenal (HPA) axis (Ellis 1966;Rivier et al. 1984;Rivier 1996), we have previously shown that the increases in both the activity of the HPA axis and in the plasma and brain concentrations of neuroactive steroids induced by an acute injection of EtOH are potentiated by social isolation (Serra et al. 2003). EtOH increases the abundance of 3a,5a-TH PROG and 3a,5a-tetrahydrodeoxycorticosterone in the brain and plasma of control rats (Barbaccia et al. 1999;Van Doren et al. 2000), an effect thought to be dependent predominantly on stimulation of the HPA axis, given that it is largely abolished after adrenalectomy (O'Dell et al. 2004). Received November 30, 2005; revised manuscript received February 6, 2006; accepted February 8, 2006.Address correspondence and reprint requests to Mariangela Serra, Department of Experimental Biology, University of Cagliari, Cagliari 09100, Italy. E-mail: mserra@unica.it Abbreviations used: ACSF, artificial cerebrospinal fluid; 3a,5a-TH PROG or AP, 3a-hydroxy-5a-pregnan-20-one; bic, bicuculline; DG, dentate gyrus; eIPSC, synaptically evoked miniature inhibitory postsynaptic current; EtOH, ethanol; GAPDH, glyceraldehyde-3-phopshate ...
Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABA A R) for c-aminobutyric acid. We now show that two different rat neuronal populations in culture manifest distinct patterns of GABA A R plasticity in response to identical stimuli. Whereas prolonged exposure to ethanol had no effect on expression of the d subunit of GABA A Rs at the mRNA or protein level in cerebellar granule neurons, it increased the abundance of d subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently downregulated d subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. These effects of ethanol exposure and withdrawal were accompanied by corresponding functional changes in GABA A Rs. GA-BA A Rs containing the d subunit were also distributed differentially in the cerebellar and hippocampal neurons. Type A receptors for c-aminobutyric acid (GABA A Rs) in mammalian neurons differ in subunit composition and function as well as manifest differential sensitivity to the natural agonist (GABA) and to various drugs and endogenous modulators (Sieghart 1995;Barnard et al. 1998;Hevers and Luddens 1998;Sieghart and Sperk 2002). The expression of distinct GABA A R subunit genes is developmentally regulated (Laurie et al. 1992a). Furthermore, whereas specific neuronal populations as well as glial cells in certain brain regions express only select GABA A R subunits (Wisden et al. 1989;Bovolin et al. 1992;Laurie et al. 1992b), other brain areas express most of the identified receptor subunits (Laurie et al. 1992a,b;Wisden et al. 1992;Pirker et al. 2000). The molecular mechanisms responsible for regulation of both the expression of the genes for the various GABA A R subunits and the assembly of specific subunit combinations to form functional receptors remain unclear (Moss and Smart 2001; Bollan et al. 2003a,b).The pattern of GABA A R gene expression is affected by environmental stimuli, physiological processes, and drugs that modulate GABA A R-mediated neurotransmission (Fenelon and Herbison 1996;Holt et al. 1996;Concas et al. 1998;Smith et al. 1998;Follesa et al. 2001;Cagetti et al. 2003;Follesa et al. 2003;Sanna et al. 2003). However, whether such induced changes in gene expression for a given GABA A R subunit are identical among different neuronal populations that express that subunit in a specific brain area is not known.Recent evidence that transient activation of synaptic GABA A Rs is responsible for conventional phasic inhibition, whereas continuous activation of extrasynaptic GABA A Rs generates a form of tonic inhibition (Brickley et al. 1996;Mody 2001;Hamann et al. 2002;Nusser and Mody 2002; Received February 14, 2005; revised
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