KIBRA-PKCγ signaling pathway modulates memory performance in mice and humans

Abstract

Human memory is a polygenic cognitive trait that is fundamental to individual competence. Genome-wide association studies (GWAS) have identified KIBRA as a novel gene associated with human memory performance. KIBRA interacts with AMPA receptors (AMPARs) and proteins essential for synaptic plasticity. The deletion of Kibra in mice impairs synaptic plasticity and learning and memory. However, the molecular basis through which KIBRA regulates dynamic AMPAR trafficking underlying synaptic plasticity is still unknown. Here we report that KIBRA interacts with the neuronal specific kinase PKCγ to modulate AMPAR trafficking upon learning, and KIBRA-PKCƔ signaling pathway also associates with human memory performance. We find PKCƔ is an essential kinase that phosphorylates AMPARs upon learning, and the loss of KIBRA in mouse brain impedes PKCƔ-AMPAR interaction. Activation of PKCƔ enables KIBRA to recruit phosphorylated AMPARs to the synapse to promote LTP and learning. We further performed transcriptomic and genetic analyses in human postmortem brain samples, and behavioral and fMRI evaluations in living human subjects, to demonstrate the genetic interactions between KIBRA and PRKCG on memory performance and memory associated physiological engagement of the hippocampal memory system. Overall, our results support that the KIBRA-PKCƔ signaling pathway is crucial for modulating memory performance in mice and humans.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

“…KIBRA-deficient mice have reduced PKMζ protein levels in the hippocampus and impaired plasticity and memory loss (41,69), which is consistent with a key role for KIBRA in PKMζ stabilization and the maintenance of synaptic plasticity. Our results show that tauKQ high mice, which have reduced KIBRA at synapses (9), also had decreased PKMζ levels in the hippocampus associated with impaired LTP and hippocampus-dependent memory.…”

“…Chemical LTP and IHC Chemical LTP experiments were performed at 14-15 days in vitro (DIV) in extracellular solution (ECS) containing (in mM): 125 NaCl, 5 KCl, 25 HEPES, 1 NaH 2 PO 4 , and 11 Glucose, and 2.5 CaCl 2 (all from Sigma-Aldrich); 0.0005 tetrodotoxin (Abcam); 0.1 picrotoxin (Caymen Chemicals); and 0.001 strychnine (Sigma-Aldrich; pH 7.4) warmed to 37°C. Rat hippocampal neurons were washed in ECS then incubated with 300 μM Glycine (Sigma-Aldrich) in ECS for 5 minutes fractions prepared from KIBRA-KO mice (69). While our study highlighted the critical role for KIBRA in modulating synapse repair to recover memory and showed that PKMζ overexpression alone was not sufficient to restore plasticity in neurons with pathogenic tau, a recent study found that the memory impairments caused by oligomeric amyloid β toxicity in rats were alleviated by PKMζ overexpression in the hippocampus (71).…”

KIBRA regulates activity-induced AMPA receptor expression and synaptic plasticity in an age-dependent manner

“…Phosphorylation is a well-established mechanism for regulating AMPAR trafficking and function. 37 , 71 In addition to serving as a signaling scaffold for regulators of endosomal trafficking, KIBRA regulates a number of kinases 50 , 60 , 72 including PKCγ 73 which was recently reported to play an important role in regulating AMPAR phosphorylation and function 73 . Identifying how different KIBRA-regulated signaling mechanisms intersect to regulate AMPARs, synaptic plasticity, and memory, and how such mechanisms change across development and celltype will be an important focus for future investigations.…”

Modulation of GABAAreceptor trafficking by WWC2 reveals class-specific mechanisms of synapse regulation by WWC family proteins

“…Despite the relevance of all WWC family proteins to disordered brain function, KIBRA is the only WWC family member that has been the subject of mechanistic study in the brain. KIBRA functions as an excitatory synapse scaffold, regulating activitydependent trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which mediate the majority of fast excitatory synaptic transmission in the brain [18][19][20][21] . Deletion of KIBRA causes aberrant trafficking and expression of AMPAR subunits GluA1 and GluA2 in the hippocampus and impairs synaptic plasticity and memory 18,19,21 .…”

“…KIBRA functions as an excitatory synapse scaffold, regulating activity-dependent trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which mediate the majority of fast excitatory synaptic transmission in the brain 18–21 . Deletion of KIBRA causes aberrant trafficking and expression of AMPAR subunits GluA1 and GluA2 in the hippocampus and impairs synaptic plasticity and memory 18,19,21 . Additionally, loss of KIBRA impairs experience-induced changes in hippocampal and cortical circuit dynamics that support memory consolidation 22…”