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

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.