is strongly upregulated during postnatal development. The upregulation of KCC2b expression is thought to be responsible for the “developmental shift” observed in mammals from depolarizing postsynaptic effects of inhibitory synapses in early neural networks to hyperpolarizing effects in mature neural networks. KCC2b knockout mice can survive up to postnatal day 17 (P17) due to the presence of functional KCC2a alone, but they exhibit low body weight, motor deficits and generalized seizures. Complete KCC2 knockouts (both KCC2a and KCC2b absent) die after birth due to respiratory failure. Oligomerization Both KCC2 isoforms can form homomultimers, or heteromultimers with other K-Cl symporters on the cell membrane to maintain chloride homeostasis in neurons. Dimers, trimers, and tetramers involving KCC2 have been identified in brainstem neurons. Oligomerization may play an important role in transporter function and activation, as it has been observed that the oligomer to monomer ratio increases in correlation to the development of the chloride ion gradient in neurons. Developmental changes in expression KCC2 levels are low during mammalian embryonic development, when neural networks are still being established and neurons are highly plastic (changeable). During this stage, intracellular chloride ion concentrations are high due to low KCC2 expression and high levels of a transporter known as NKCC1 (Na+/K+ chloride cotransporter 1), which moves chloride ions into cells. Thus, during embryonic development, the chloride gradient is such that stimulation of GABAA receptors and glycine receptors at inhibitory synapses causes chloride ions to flow out of cells, making the internal neuronal environment less negative (i.e. more depolarized) than it would be at rest. At this stage, GABAA receptors and glycine receptors act as excitatory rather than inhibitory effectors on postsynaptic neurons, resulting in depolarization and hyperexcitability of neural networks. During postnatal development, KCC2 levels are strongly upregulated while NKCC1 levels are down regulated. This change in expression correlates to a developmental shift of the chloride ion concentration within neurons from high to low intracellular concentration. Effectively, as the chloride ion concentration is reduced, the chloride gradient across the cellular membrane is reversed such that GABAA receptor and glycine receptor stimulation causes chloride ion influx, making the internal neuronal environment more negative (i.e. more hyperpolarized) than it would be at rest. This is the developmental shift of inhibitory synapses from the excitatory postsynaptic responses of the early neural development phase to the inhibitory postsynaptic responses observed throughout maturity. Function Current literature suggests that KCC2 serves three