Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review
Introduction
Recent studies have implicated cation-chloride cotransporters (CCCs) in molecular mechanisms underlying disorders of the central and peripheral nervous systems (CNS and PNS, respectively), including spasticity (Boulenguez et al., 2010; Toda et al., 2014), seizures, epilepsy (Puskarjov et al., 2014; Woo et al., 2002), allodynia, and neuropathic pain (Coull et al., 2003; Tsuda et al., 2003; Zhou et al., 2012).
In most mature neurons, intracellular Cl− ([Cl−]i) is maintained at low concentrations by channels and transporters; in most neurons, this is performed only by the K+-Cl- cotransporter 2 (KCC2) (Blaesse et al., 2009; Rivera et al., 1999). However, in immature neurons, [Cl−]i is maintained at relatively high levels due to the inhibition of KCC2 expression. Therefore, GABAA and glycine receptors, which act as inhibitory receptors in mature neurons, serve a “depolarizing” function in immature neurons (Rivera et al., 1999). In diseases of the CNS and PNS, alterations in KCC2 expression disrupt the normally low [Cl−]i found in mature neurons. High [Cl−]i results in hyperexcitability in the damaged mature neurons.
Changes in KCC2 expression have been associated with brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). Interestingly, the BDNF-TrkB pathway has been implicated in both the pathological development and functional amelioration of various neuronal disorders (Boulenguez et al., 2010; Rivera et al., 2004; Tashiro et al., 2015); and the overexpression of BDNF reportedly worsens pathological conditions (Boyce et al., 2012; Ziemlinska et al., 2014). However, recent reports have suggested that rehabilitation through exercise and mechanical stimulation can normalize the expression of KCC2 and thus improve the symptoms of neuronal disorders (Hahm et al., 2015; Hou et al., 2014; Tashiro et al., 2015).
In the present review, we summarize the recent progress regarding the roles of Cl− regulators in immature and mature neurons, as well as the role of KCC2 regulation via the BDNF-TrkB pathway in spinal cord injury and rehabilitation.
Section snippets
Regulation of [Cl−]i in neurons
In mature neurons, the levels of [Cl−]i is regulated by several ion channels and transporters: 1) ligand-gated ion channels, such as GABAA and glycine receptors; 2) voltage-gated Cl− channels, such as ClC channels; 3) calcium-activated Cl− channels, such as anoctamin channels; 4) pH-sensitive Cl− channels, such as SLC4, SLC26, and CFTR (cystic fibrosis transmembrane conductance regulator) channels; and 5) CCCs, such as KCC2 and NKCC1 (Fig. 1) (Rahmati et al., 2018). Cl− ions move across the
Role of KCC2 in developing and mature neuronal states
KCC2 expression is regulated via transcriptional and post-translational mechanisms. The transcriptional regulation of KCC2 expression can exert different effects on neuronal maturation.
Regulation of KCC2 expression and synaptic signaling after neuronal trauma
In models of neuropathic pain after PNS nerve and spinal cord injuries, activated microglial cells secrete BDNF into the extracellular space, where it binds to neuronal TrkB. Thus, in damaged neurons, KCC2 expression is downregulated following activation of both the PLCγ1 and Shc signaling cascades of the BDNF-TrkB pathway (Beggs et al., 2012; Coull et al., 2005; Kaila et al., 2014; Tsuda et al., 2003) (Fig. 5). In contrast, significant increases in the levels of activated microglia are
Effect of rehabilitation on injury-induced downregulation of KCC2
For the treatment of KCC2 in molecular mechanisms underlying disorders of CNS and PNS, damaged neurons are infused with exogenous BDNF to induce upregulation of KCC2 expression. However, upregulation of endogenous BDNF via rehabilitation strategies (e.g., exercise and mechanical stimulation) has been reported to promote recovery of KCC2 expression and improve spasticity and pain following injury.
Tashiro and colleagues (Tashiro et al., 2015) reported that 2 weeks of gait training (70–80% weight
Conclusion
The downregulation of KCC2 that underlies disorders of the CNS and PNS may be reversed by targeting the BDNF-TrkB. However, signaling cascades of compensatory KCC2 upregulation have not yet been identified and should thus be explored by future research. On the other hand, KCC2 selective analogs CLP257 and CLP 290, which is a carbamate prodrug of CLP257, have been found to activate KCC2 and thereby treat neuropathic pain and spinal cord injury (Chen et al., 2018; Gagnon et al., 2013). While the
Declaration of interest
None.
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Pax3 induces target-specific reinnervation through axon collateral expression of PSA-NCAM
2024, Progress in NeurobiologyTrifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through α7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats
2023, Biomedicine and PharmacotherapyCitation Excerpt :Further studies confirm that activation of BDNF/TrkB signaling is highly related to GABAergic neurons [16,17]. For example, within peripheral nerve injury states, the activated BDNF/TrkB cascade in the spinal cord can promote a reduction of K+-Cl- co-transporter 2 (KCC2) and its alterations of structure and function, contributing to central sensitization [18–20]. Currently, the studies on the pathophysiological mechanisms of neuropathic pain mainly focus on neurotransmitters and its receptors evoked pain hypersensitivity, signal molecules and the interaction between microglia and neurons, thereby targeting these signal molecules may be potential therapeutic candidates against neuropathic pain.
BDNF modulated KCC2 ubiquitylation in spinal cord dorsal horn of mice
2021, European Journal of PharmacologyCitation Excerpt :KCC2 dysfunction in the dorsal horn neurons has been known as a key player in spinal disinhibition and neuropathic pain (Coull et al., 2003; Mapplebeck et al., 2019). Nerve injuries stimulate glial cells to release BDNF, which in turn activates TrkB receptors expressed on nociceptive neurons to decrease KCC2 function through multiple pathways, including phospholipase C-dependent inhibition of kcc2 mRNA transcription and calpain-mediated irreversible cleavage of KCC2 protein (Coull et al., 2003; Lee-Hotta et al., 2019; Mapplebeck et al., 2019; Puskarjov et al., 2012). The major finding of current study was that BDNF was able to activate Cbl-b, an E3 ubiquitin ligase that conjugated KCC2 with Lys48-linked ubiquitin chains and contributed to KCC2 downregulation.