Pro-Brain-Derived Neurotrophic Factor (proBDNF)-Mediated p75NTR Activation Promotes Depolarizing Actions of GABA and Increases Susceptibility to Epileptic Seizures

Abstract

The brain-derived neurotrophic factor (BDNF) is synthesized as a precursor, namely proBDNF, which can be processed into mature BDNF (mBDNF). Evidences suggest that proBDNF signaling through p75NTR may account for the emergence of neurological disorders. These findings support the view that the relative availability of mBDNF and proBDNF forms is an important mechanism underlying brain circuit formation and cognitive functions. Here we describe novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating neuronal circuit and synaptic plasticity during the first postnatal weeks in rats. Our results showed that increased proBDNF/p75NTR signaling during development maintains a depolarizing γ-aminobutyric acid (GABA) response in a KCC2-dependent manner in mature neuronal cells. This resulted in altered excitation/inhibition balance and enhanced neuronal network activity. The enhanced proBDNF/p75NTR signaling ultimately led to increased seizure susceptibility that was abolished by in vivo injection of function blocking p75NTR antibody. Altogether, our study shed new light on how proBDNF/p75NTR signaling can orchestrate the GABA excitatory/inhibitory developmental sequence leading to depolarizing and excitatory actions of GABA in adulthood and subsequent epileptic disorders.

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 change in the regulation of GABA A Rs cell surface expression by BDNF coincides with a shift in GABA polarity (depolarization to hyperpolarization), attributed to the activity of KCC2 (Rivera et al, 1999) which is also regulated by both forms of BDNF. A recent study showed that increased proBDNF/p75 NTR signaling disrupts the developmental GABAergic sequence by maintaining a depolarizing GABA response in a KCC2-dependent manner in mature cortical neurons (Riffault et al, 2018). In developing neurons, BDNF increases KCC2 expression on the level of mRNA transcription (Aguado et al, 2003; Rivera et al, 2004; Ludwig et al, 2011).…”

“…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).…”