Regulation of AMPA Receptor Function by the Human Memory-Associated Gene KIBRA

Abstract

KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in non-neuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.

Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals

“…KIBRA encodes a phosphoprotein, which binds to many proteins including those implicated in neuronal and synaptic plasticity, cell migration, vesicular transport, mitosis and tumorigenesis (Zhang et al, 2014). It has been proposed that KIBRA regulates AMPA receptors, the major excitatory synaptic receptors of the brain, suggesting KIBRA may be involved in synaptic plasticity and transmission (Makuch et al, 2011;Zhang et al, 2014). CLSTN2 is part of the components of the postsynaptic membrane and is located predominately in excitatory synapses giving CLSTN2 a role in intracellular postsynaptic signaling, potentially mediating specific responses in excitatory synaptic transmission (Hintsch et al, 2002).…”

KIBRA Regulates Aurora Kinase Activity and Is Required for Precise Chromosome Alignment During Mitosis

“…KIBRA was originally identified as a memory performance-associated protein in humans (28 -32), and this function was recently confirmed in mice (33). The physiological function of KIBRA in non-neuronal cells is much less defined, although KIBRA has been shown to be involved in cell migration in podocytes (34) and NRK cells (35) and in epithelial cell polarity (36).…”

WWC1 (WW and C2 domain containing 1)

“…A recent study using KIBRA-knockout mice showed that KIBRA is necessary for the contextual and trace fear memory in adult mice (Makuch et al, 2011). KIBRA is also associated with Alzheimer's disease and recurrent depressive disorders (Corneveaux et al, 2008;Galecki et al, 2010).…”