Depolarizing γ‐aminobutyric acid contributes to glutamatergic network rewiring in epilepsy

Abstract

Our findings show that early post-SE abnormal depolarizing GABA and p75 signaling fosters a long-lasting rearrangement of glutamatergic network that contributes to the epileptogenic process. This finding defines promising and novel targets to constrain reactive glutamatergic network rewiring in adult epilepsy. Ann Neurol 2017;81:251-265.

Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains

“…In patients with temporal lobe epilepsy, the decrease in KCC2 expression results in depolarizing GABAergic events in a minority of subicular pyramidal cells that contribute to inter-ictal like activity (Cohen et al, 2002; Huberfeld et al, 2007). These findings are consistent with reports of KCC2 downregulation and changes in the polarity of GABAergic response in animal models of epilepsy (Huberfeld et al, 2007; Barmashenko et al, 2011; Shimizu-Okabe et al, 2011; Kourdougli et al, 2017; Riffault et al, 2018). Because both forms of BDNF regulate the expression of KCC2 (Rivera et al, 1999; Ludwig et al, 2011), the decrease observed in epileptic tissues could be due to an imbalance between mBDNF/TrkB and proBDNF/p75 NTR signaling during the first postnatal weeks causing an impaired or delayed functional maturation of GABAergic inhibition.…”

“…The elevated amounts of proBDNF following SE are associated with reduced proBDNF cleavage machinery that results from acute decreases in tPA/plasminogen proteolytic cascade and increases in API-1, an inhibitor of proBDNF cleavage (Reibel et al, 2000; Binder et al, 2001). Furthermore, two recent studies showed that proBDNF/p75 NTR response following SE selectively downregulates KCC2, which in turn promotes a chloride homeostasis dysregulation leading to an excitatory action of GABA A receptors and facilitate epileptiform discharges (Kourdougli et al, 2017; Riffault et al, 2018; Figure 2). Interestingly, blockade of p75 NTR during the earliest phase of epileptogenesis restores KCC2 levels and reduces seizures frequency (Kourdougli et al, 2017; Riffault et al, 2018).…”

“…Furthermore, two recent studies showed that proBDNF/p75 NTR response following SE selectively downregulates KCC2, which in turn promotes a chloride homeostasis dysregulation leading to an excitatory action of GABA A receptors and facilitate epileptiform discharges (Kourdougli et al, 2017; Riffault et al, 2018; Figure 2). Interestingly, blockade of p75 NTR during the earliest phase of epileptogenesis restores KCC2 levels and reduces seizures frequency (Kourdougli et al, 2017; Riffault et al, 2018). These results suggest that proBDNF/p75 NTR play a critical role in the mechanisms of epileptogenesis (see Figure 2).…”

“…At the transcriptional level, BDNF/TrkB signaling causes the repression of GABA A Rs α1 subunit gene through the activation of JAK-STAT pathway following SE (Lund et al, 2008). An important feature of epileptogenesis is a downregulation of KCC2 expression both in human epileptogenic tissues (Aronica et al, 2007; Huberfeld et al, 2007; Munakata et al, 2007; Shimizu-Okabe et al, 2011; Kahle et al, 2014) and in animal models of epilepsy (Jin et al, 2005; Kourdougli et al, 2017; Riffault et al, 2018). In patients with temporal lobe epilepsy, the decrease in KCC2 expression results in depolarizing GABAergic events in a minority of subicular pyramidal cells that contribute to inter-ictal like activity (Cohen et al, 2002; Huberfeld et al, 2007).…”

Probing the polarity of spontaneous perisomatic GABAergic synaptic transmission during epileptogenesis in the mouse CA3 circuit in vivo

“…In vivo treatment with the diuretic bumetanide, which also reduces the accumulation of Clions in neurons through the inhibition of the Clintruder NKCC1, was found to reduce behavioural abnormalities in rat and mouse models of Autism Spectrum Disorders (5) and seizures in animal models of epilepsy (19,(29)(30)(31)(32)(33). But bumetanide has a limited bio-availability in the brain due to poor blood brain barrier penetration (34)(35)(36), and it is finally unclear if its action in vivo was indeed due to the restoration of neuronal Clgradient and inhibitory GABAergic transmission.…”