New connections: Neurodevelopmental switches

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Science Signaling  30 Jun 2020:
Vol. 13, Issue 638, eabd5218
DOI: 10.1126/scisignal.abd5218

Protein modifications in neurons during early development regulate pain sensation and cognition.

Various “critical windows” occur during embryonic, prenatal, and postnatal development, not least in the nervous system. In addition to what we know about the impact of dysregulated gene expression on neurodevelopment, several papers in Science Signaling show how failure to switch on—or off—protein activity in developing neurons can alter neuronal function. In this issue, Zhang et al. uncovered a ubiquitin-mediated switch involving N-methyl-d-aspartate (NMDA) receptor composition that controls neuronal sensitivity. The authors found that the amount of the NMDA receptor subunit GluN2B in sensory neurons of the spine was progressively restricted during early postnatal development in mice and maintained at low abundance during adulthood by the E3 ubiquitin ligase Cbl-b. However, peripheral inflammation reverted this developmental switch by inducing the dephosphorylation of Cbl-b, which impaired its interaction with GluN2B. The consequential increase in GluN2B abundance enhanced NMDA receptor activity and animals’ sensitivity to touch. Identifying a way to target this mechanism might be therapeutic in patients suffering from inflammatory neuropathy. In the Archives, Watanabe et al. and Pisella et al. (see also the Focus by Zamponi) elucidated the role of the channel KCC2 in social and cognitive neurodevelopment. Using knockin mouse models that expressed a mutant KCC2 that mimics the phosphorylated form, the authors found that perinatal dephosphorylation of two threonine sites in KCC2 was critical for an excitatory-to-inhibitory switch in the response of neurons to the neurotransmitter GABA. This switch promotes the neurocircuitry that underlies cognition, respiration, and other critical aspects of neurological physiology. These findings may provide clues to the causes of KCC2 (SLC12A5)–related pathologies in humans, including epilepsy, schizophrenia, and Rett syndrome.

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