Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis.

Zsolt Kovács,Zsolt Szabó,Pál T Szabó,Krisztina Németh,Rüdiger W Veh,László Héja,Serguei N Skatchkov,Julianna Kardos

doi:10.3389/fncel.2021.787319

Abstract

Accumulating evidence indicate that astrocytes are essential players of the excitatory and inhibitory signaling during normal and epileptiform activity via uptake and release of gliotransmitters, ions, and other substances. Polyamines can be regarded as gliotransmitters since they are almost exclusively stored in astrocytes and can be released by various mechanisms. The polyamine putrescine (PUT) is utilized to synthesize GABA, which can also be released from astrocytes and provide tonic inhibition on neurons. The polyamine spermine (SPM), synthesized form PUT through spermidine (SPD), is known to unblock astrocytic Cx43 gap junction channels and therefore facilitate astrocytic synchronization. In addition, SPM released from astrocytes may also modulate neuronal NMDA, AMPA, and kainate receptors. As a consequence, astrocytic polyamines possess the capability to significantly modulate epileptiform activity. In this study, we investigated different steps in polyamine metabolism and coupled GABA release to assess their potential to control seizure generation and maintenance in two different epilepsy models: the low-[Mg2+] model of temporal lobe epilepsy in vitro and in the WAG/Rij rat model of absence epilepsy in vivo. We show that SPM is a gliotransmitter that is released from astrocytes and significantly contributes to network excitation. Importantly, we found that inhibition of SPD synthesis completely prevented seizure generation in WAG/Rij rats. We hypothesize that this antiepileptic effect is attributed to the subsequent enhancement of PUT to GABA conversion in astrocytes, leading to GABA release through GAT-2/3 transporters. This interpretation is supported by the observation that antiepileptic potential of the Food and Drug Administration (FDA)-approved drug levetiracetam can be diminished by specifically blocking astrocytic GAT-2/3 with SNAP-5114, suggesting that levetiracetam exerts its effect by increasing surface expression of GAT-2/3. Our findings conclusively suggest that the major pathway through which astrocytic polyamines contribute to epileptiform activity is the production of GABA. Modulation of astrocytic polyamine levels, therefore, may serve for a more effective antiepileptic drug development in the future.

Highlights

Polyamines are polycationic molecules that perform various functions in the brain from maintenance of redox balance (Murray-Stewart et al, 2018), through direct regulation of ion channels (Herman et al, 1993; Biedermann et al, 1998; Weiger et al, 1998; Skatchkov et al, 2006; Kucheryavykh et al, 2008; Nichols and Lee, 2018) and various subtypes of glutamate receptors (GluR) (Benveniste and Mayer, 1993; Williams, 1997; Mott et al, 2003), to modulation of higher cognitive functions (Guerra et al, 2016)
Such network is developed after six postnatal days (Harris and Teyler, 1983) and is sensitive to polyamine synthesis, when PUT synthesis was blocked by depressed by applying alfadifluoromethylornithine (DFMO) (Ferchmin et al, 1993)
We explored whether various interventions modifying the astrocytic polyamine concentrations can be effective against epileptiform discharges in the low-[Mg2+] in vitro model of temporal lobe epilepsy (TLE) and in the in vivo WAG/Rij rat model of absence epilepsy

Summary

Introduction

Polyamines are polycationic molecules that perform various functions in the brain from maintenance of redox balance (Murray-Stewart et al, 2018), through direct regulation of ion channels (Herman et al, 1993; Biedermann et al, 1998; Weiger et al, 1998; Skatchkov et al, 2006; Kucheryavykh et al, 2008; Nichols and Lee, 2018) and various subtypes of glutamate receptors (GluR) (Benveniste and Mayer, 1993; Williams, 1997; Mott et al, 2003), to modulation of higher cognitive functions (Guerra et al, 2016). Polyamines have been suggested to either directly target AMPARs (Rozov and Burnashev, 1999), Ca2+ channels (Herman et al, 1993; Ferchmin et al, 1995), NMDARs (Benveniste and Mayer, 1993), Kir channels (Lopatin et al, 1994, 1995; Nichols and Lopatin, 1997; Skatchkov et al, 2000, 2002; Kucheryavykh et al, 2007, 2008), TRPV channels (Ahern et al, 2006), Cx43 GJCs (Skatchkov et al, 2015; Kucheryavykh et al, 2017), or ASIC channels (Duan et al, 2011). Spermidine (SPD) protects from age-related alterations of synapses via autophagy mechanism (Sigrist et al, 2014; Maglione et al, 2019), data on the release of polyamines from astrocytes with consequent effect on neighboring inhibitory interneurons were reported only in astrocyte culture (Malpica-Nieves et al, 2021)

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