From Synapses to Circuits, the Role of KIBRA and the WWC Family in Adaptive Brain Function

ABSTRACT KIBRA ( WWC1 ) has been a subject of scientific interest and investigation for almost two decades following its initial association with nonpathological variation in human memory performance. Work in a variety of animal models confirms that KIBRA supports memory function and demonstrates that regulation of AMPA‐type glutamate receptors is a key mechanism by which KIBRA modulates neuronal function. KIBRA is a scaffolding protein at excitatory synapses, and its interactome is enriched for proteins that regulate AMPA receptor (AMPAR) trafficking and synaptic plasticity as well as neurodevelopmental disorders. Here, I provide a comprehensive discussion of known and potential mechanisms by which KIBRA and its interactome regulate adaptive brain function, encompassing AMPAR trafficking, synaptic plasticity, and experience‐induced modification of circuit dynamics. Disrupted KIBRA function is implicated in a variety of cognitive disorders, and I review mechanisms by which KIBRA may contribute to neuropathology as well as recent work suggesting that KIBRA manipulation may be a target for cognitive enhancement. I expand the discussion to include recent data identifying the KIBRA homolog WWC2 as a regulator of GABA A receptor expression at inhibitory synapses. In contrast to their distinct roles at excitatory and inhibitory synapses, KIBRA and WWC2 promote dendritic arborization in a non‐redundant manner, and I discuss potential shared mechanisms by which WWC proteins regulate neuronal morphology as well as evidence that this function of WWC proteins may be disrupted in neurodevelopmental pathology. image