The memory gene KIBRA is a bidirectional regulator of synaptic and structural plasticity in the adult brain.

Memory formation is associated with activity-dependent changes in synaptic plasticity. The mechanisms underlying these processes are complex and involve multiple components. Recent work has implicated the protein KIBRA in human memory, but its molecular functions in memory processes remain not fully understood. Here, we show that a selective overexpression of KIBRA in neurons increases hippocampal long-term potentiation (LTP) but prevents the induction of long-term depression (LTD), and impairs spatial long-term memory in adult mice. KIBRA overexpression increases the constitutive recycling of AMPA receptors containing GluA1 (GluA1-AMPARs), and favors their activity-dependent surface expression. It also results in dramatic dendritic rearrangements in pyramidal neurons both in vitro and in vivo. KIBRA knockdown in contrast, abolishes LTP, decreases GluA1-AMPARs recycling and reduces dendritic arborization. These results establish KIBRA as a novel bidirectional regulator of synaptic and structural plasticity in hippocampal neurons, and of long-term memory, highly relevant to cognitive processes and their pathologies.

Activity pattern-dependent long-term potentiation in neocortex and hippocampus of GluA1 (GluR-A) subunit-deficient mice.

The AMPA receptor subunit GluA1 (GluR-A) has been implicated to be critically involved in the expression of long-term potentiation (LTP) and memory formation. Mice lacking this subunit possess a profound spatial working memory deficit. We investigated the influence of the GluA1 subunit on the expression of LTP in pyramidal neurons of the hippocampus CA1 region and somatosensory cortex layer 2/3 for different cellular LTP protocols in adult mice. We found that the GluA1 subunit was not required for LTP in cortical pyramidal neurons. In contrast, GluA1-dependent LTP expression in CA1 pyramidal neurons was differentially dependent on the LTP induction parameters. Depolarization pairing was exclusively, theta-burst pairing was partially, and spike-timing-dependent plasticity (STDP) was independent of the GluA1 subunit. Spike-timing-dependent LTP required postsynaptic membrane fusion in CA1 pyramidal neurons. We conclude that during LTP induction at the hippocampal CA3-to-CA1 synapse the recruitment of the GluA1 subunit is controlled by particular electrical activity patterns that might reflect specific behavioral states. Furthermore, other LTP expression mechanisms exist that do not require the presence of GluA1. The previously reported spatial working memory deficits in GluA1-lacking mice (Gria1(-/-) mice) together with these results suggest that STDP might be a likely basis for the formation of spatial reference memory whereas it is not required for the rapid formation of spatial working memory where a fast but transient increase of synaptic efficacy might be needed.