KCC2 regulates dendritic spine development

Neuron-specific potassium-chloride cotransporter KCC2 operates both as an ion transporter crucial for establishment of hyperpolarizing inhibitory responses and as a structural protein that regulates development of dendritic spines and glutamatergic synapses. The latter function is mediated through interaction with synaptic proteins and it is entirely independent of KCC2 ion transport function. Among KCC2 binding partners are actin-associated protein 4.1N and Rac1 guanine-nucleotide exchange factor β-PIX, the two proteins mediating the role of KCC2 in spines. KCC2 interaction with 4.1N is essential for the morphological and functional maturation of dendritic spines. Indeed, through binding to 4.1N, KCC2 controls organization of sub-membrane actin cytoskeleton and diffusion of glutamate receptors at spine synapses. In addition, the interaction with β-PIX provides KCC2 with a pathway to regulate actin dynamics. Through β-PIX, KCC2 affects the activity of small GTPase Rac1 and phosphorylation of actin-depolymerizing protein cofilin-1. KCC2- β-PIX interaction plays a crucial role in synaptogenesis and formation of spines, as well as in activity-dependent plasticity of glutamatergic synapses. Thus, through two independent mechanisms, the upregulation of KCC2 during development leads to maturation of inhibitory neurotransmission and, in parallel, to formation of excitatory synapses and morphogenesis of dendritic spines. In other words, KCC2 is involved in the coordinated functional development of excitatory and inhibitory neurotransmission. In the mature brain, a similar synchronizing role may be employed in processes that require coordinated changes of excitation and inhibition.