KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Abstract

Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K+-Cl− cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

“…Although the actual mechanisms that control the developmental expression of chloride cotransporters are not clear, MeCP2 is known to regulate neuronal activity-dependent expression of BDNF (27), which promotes the developmental up-regulation of KCC2 (89) and the maturation of cortical inhibition (88). Overexpression of KCC2 in MeCP2-deficient human neurons differentiated from induced pluripotent stem cells from patients with RTT has recently been shown to rescue GABA functional deficits (90). Neuronal Cl − regulation through KCC2 thus offers an attractive target for postsynaptic modulation of inhibition in RTT.…”

APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

“…KCC2 maintains low [Cl - ] i in mature neurons, which is essential for maintaining proper postsynaptic inhibition mediated by GABA A receptors (GABA A Rs) and glycine receptors (GlyRs) (Braat and Kooy, 2015a; Kaila et al, 2014; Rivera et al, 1999). Impaired KCC2 activity and subsequent increases in [Cl - ] i occur in several neurological disorders (Boulenguez et al, 2010; Coull et al, 2003; Tang et al, 2016), leading to a depolarizing action of GABA A R mediated currents due to a positive shift of E GABA , and over-excitation of neuronal network activity (Ben-Ari, 2002; Ben-Ari et al, 2012; Blaesse et al, 2009). Recent experiments on KCC2 processing suggest that the intrinsic ion transport rate, cell surface stability, and trafficking of plasmalemmal KCC2 are rapidly and reversibly modulated by the (de)phosphorylation of critical serine and tyrosine residues at the C-terminus of this protein (Lee et al, 2010, 2007).…”

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

“…Djuric et al 86 , went on to also show that RTT neurons had decreased cell capacitance, dysfunction in action potential generation, dysfunction in voltage-gated sodium currents, and dysfunction in miniature excitatory synaptic current frequency and amplitude. Two studies demonstrated particularly well the power of hiPSCs by showing that RTT neurons had a delayed functional switch in GABA from excitatory to inhibitory 84 and neuronal progenitors from RTT patients had an increased frequency of L1 retrotranspositions 83 , conclusions almost impossible to derive from any other experimental medium. Tang et al went on further to show that IGF1 treatment rescued GABA functional deficits 84 .…”

“…Two studies demonstrated particularly well the power of hiPSCs by showing that RTT neurons had a delayed functional switch in GABA from excitatory to inhibitory 84 and neuronal progenitors from RTT patients had an increased frequency of L1 retrotranspositions 83 , conclusions almost impossible to derive from any other experimental medium. Tang et al went on further to show that IGF1 treatment rescued GABA functional deficits 84 . In addition, Rett gain of function by gene duplication (MECP2dup) has also been modeled in hiPSC lines, showing a phenotype in many respect opposite to that of Rett loss of function, namely increased synaptogenesis and dendritic complexity along with altered neuronal network synchrony 73 .…”