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Reactive Astrogliosis in Epilepsy -Passive Bystanders No More Journal of Neurology & Stroke Reactive Astrogliosis in Epilepsy -Passive Bystanders no more Keywords: 1-Integrin Commentary Astrogliosis; Temporal Lobe Epilepsy; Gfap; β Introduction Volume 5 Issue 4 - 2016 Department of Neurology, Montefiore Medical Center, USA Temporal lobe epilepsy (TLE) is a neurological disorder that is characterized by spontaneous, recurrent seizures and can be *Corresponding author: andassociated biochemistry with reactive of astrocytes astrogliosis and is(also important known foras astrocytosis). tissue repair Sloka S Iyengar, Department of This is an adaptive process that consists of alterations in structure Neurology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, 583W, 215th street, Apt A2, New York, and regulation of inflammation. Anti-epileptic drugs (AEDs) USA, Tel: (803) 235-1116; Email: used to manage TLE can be associated with refractoriness and Received: October 04, 2016 | Published: reactivesubstantial astrogliosis side-effects. in epilepsyMost AEDs could act lead through to development mechanisms of 2016 December 20, that primarily involve neurons; hence, examining the role of in epilepsy is not well understood, as experiments suggest both potentialnovel therapies pro- andfor epilepsy. anti-epileptogenic The exact role effects of reactive [1,2]. astrogliosisGiven that - -/- mice also exhibited hyperexcitability in pyramidal sprouting and changes in receptor and neurotransmitter function, cellsjneurosci.org/content/35/8/3330/F3.expansion.html of layer II/III of the cortex in response in two models). Brain of sli in epilepsy can be associated with neurodegeneration, mossy fiber vitroces from β1 - -/- - examining the specific role of reactive astrogliosis in epilepsy has tion of epileptiform action potentials activity, in responsewhere a reduced to current latency injection to the and first input ic radialbeen fraught glia caused with reactive difficulties. astrogliosis Previously, marked a transgenic by hypertrophy mouse andline tal and non-ictal event in slices from β1 mice was seen. Examina was generated [3] where deletion of β1-integrin preferentially in -/- mice were more excitable than slices from mouse line, in the current Journal of Neuroscience study [4], the output (I/O) curves also showed that Layer II/III pyramidal cells- authorsupregulation examined of astrocyte-specific whether reactive markers. astrogliosis Using thisby transgenicitself was in the cortex of β1 control mice. But how does one know that these results are spe would be. cific to astrocytes? To address this, the authors used mice where- sufficient to cause epilepsy, and what the underlying mechanisms rexcitabilityβ1-integrin wasin response deleted fromto Mg neurons2+ instead of radial glia (β1-- In all experiments, control mice were compared to those with /- Nex::Cre mice) and found that these mice did not exhibit hype- pansion.html -free aCSF (artificial cerebrospi nal fluid: http://www.jneurosci.org/content/35/8/3330/F4.ex reactive astrogliosis caused by deletion of β1-integrin in radial - ). However, examining whether β1-/- Nex::Cre mice glia (‘β1-/- mice’). First, reactive astrogliosis was qualitatively exhibit spontaneous seizures would have been quite informative.in vitro and quantitatively confirmed in the cortex of β1-/- mice at va -/- mice, the authors examined glutamate couldrious ages.be an β1-/- independent mice also process had microglial as well activation;(http://www.jneurosci. this could be uptakeTo explore and homeostasis possible reasons of K+ and underlying epilepsy and a consequence of reactive astrogliosis as the authors suggest, but- roleepileptiform in tightly activity regulating in β1 K+ indeed increasing K+ concentrationCl- is ions. an in Astrocytes vitro model play of inducinga critical org/content/35/8/3330/F1.expansion.html). EEG analysis reve epileptiform activity. Kir4.1 channelshomeostasis mediate in the K normal+ conductance brain; aled that a subset of β1-/- mice exhibited spontaneous seizures;- and conditional knockout of Kir4.1 channels in astrocytes is interestingly, there was a correlation between levels of GFAP and- seizure frequency. Interictal spikes (IIS) - the hallmark of an epi this, tissue from people with hippocampal sclerosis was found to leptic brain- were also found in β1-/- mice (http://www.jneuros- haveassociated abnormally with greater high level propensity of extracellular to seizures K+ [6]. [5]. In In the line current with ci.org/content/35/8/3330/F2.expansion.html). The authors here study, K+ -/- mice was studied by recording from examined only convulsive seizures or tonic-clonic seizures. Howe astrocytes(http://www.jneurosci.org/content/35/8/3330/ ver, analyzing subconvulsive seizures that also occur clinically homeostasis in β1 + homeostasis showed would have given more complete information about the seizure wereprofile. due Since to reactivejust implanting astrogliosis electrodes or because can cause of a seizuresphysical dueinjury to F5.expansion.html), and parameters of K excitotoxicity, the next question was to examine whether seizures modest deficiencies in mice with reactive astrogliosis. uptake [7] - a single astrocyte can release enough glutamate to Astrocytes are the primary cell type responsible for glutamate to -/-the brain caused by EEG electrodes. Indeed, control mice with glutamate in the hippocampus has been observed in human extentimplanted of damage electrodes caused did by not electrode show spontaneous implantation seizures, (http://www. and in depolarize 2-4 adjacent neurons. An increased intracellular β1 mice, the incidence of seizures and IIS was unrelated to the Submit Manuscript | http://medcraveonline.com J Neurol Stroke 2016, 5(4): 00186 Copyright: Reactive Astrogliosis in Epilepsy -Passive Bystanders no more ©2016 Iyengar 2/2 +. in glutamate transporters, glutamate uptake was vastly decreased, suggestingepileptic tissue increased [8]. In β1-/-extracellular mice, though glutamate there wereas a fewcontributor changes by enabling efficient removal of extracellular glutamate and K of hyperexcitability studyA breakdown [11] compared in the gap tissue junction from couplingpatients betweenwith hippocampal astrocytes necessary for degradation of glutamate into glutamine and for could then cause hyperexcitability and perhaps seizures. A recent . Glutamine synthetase (GS) - an enzyme showed an uncoupling of astrocytes. In a mouse model of epilepsy, -/- mice (http://www.jneurosci.org/content/35/8/3330/ sclerosis (HS) to those without HS, and found that all HS patients providing precursors for the production of GABA - was reduced profound astrocyte uncoupling, which was observed as early as thein β1authors examined the inhibitory system, as the presence of administration of inflammatory mediators was able to cause F6.expansion.html). After exploring excitatory neurotransmission, could possibly predict who with traumatic brain injury develops epilepsy4 hours post-status later on. In epilepticus; summary, hence,this Journal early astrocyteof Neuroscience uncoupling [4] Clepileptiform- co-transporters activity NKCC1 could andrepresent KCC2, anand imbalance alterations in inGABAergic the ratio study provides data suggesting that epilepsy could be viewed as a neurotransmission. GABAergic transmission is regulated by two have been shown in neuronal development and epilepsy [9]. lead to better therapies for epilepsy and associated comorbidites. of these co-transporters so as to confer GABA a depolarizinghttp:// effect glial - and not neuronal - dysfunction. Hence, targeting glia could References Similarly, in this study, the authors found increased NKCC1 ( 1. ofwww.jneurosci.org/content/35/8/3330/F7.expansion.html this alteration in Cl- cotransporter ratio would be interesting). Although not examined here, the electrophysiological correlate Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, et al. (2004) Reactive astrocytes sprotect tissue and preserve function after 2. to see.-/- Administrationmice (http://www.jneurosci.org/content/35/8/3330/ of bumetanide - a drug that blocks spinal cord injury. J Neurosci 24(9): 2143-2155. NKCC1 showed a reversal in the seizure phenotype in a subset Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, et al. (2010) of β1 Selective induction of astrocytic gliosis generates deficits in neuronal leastF8.expansion.html partly due to). aberrationsIn summary, in this glutamate is the firstuptake study and to Cl show- co- 3. inhibition. Nat Neurosci 13(5): 584-591. that global reactive astrogliosis is sufficient to cause seizures, at deletion of beta1-integrin in astroglia causes partial reactive gliosis. Robel S, Mori T, Zoubaa S, Schlegel J, Sirko S, et al. (2009) Conditional transporters. This was found in the absence of blood brain barrier 4. Glia 57(15): 1630-1647. (BBB) compensation, which is important because BBB breach can cause or exacerbate seizures by itself. Robel S, Buckingham SC, Boni JL, Campbell SL, Danbolt NC, et al. (2015) Reactive astrogliosis causes the development of spontaneous Reactive astrogliosis in this study was induced by deleting-/- mice β1- 5. seizures. J Neurosci 35(8): 3330-3345. Conditional knock-out of Kir4.1 leads to glial membrane integrin from radial glia at birth. Since radial glia are critical for Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) neuronal migration, examining neuronal migration in β1 could have helped rule out effects of mismigration on seizures. 11354-11365.depolarization, inhibition of potassium and glutamate uptake, and This
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