Regulation Of Hippocampal NMDA Receptor Signaling, Memory And Synaptic Plasticity By The JIP1 Scaffold Protein

Abstract

Learning and memory rely upon mechanisms of activity-dependent plasticity such as hippocampal long-term potentiation (LTP) and long-term depression (LTD). At least six types of plasticity exist to function as various types of coincidence detectors. Ultimately, plasticity signaling at the synapse flows, among other pathways, through mitogen-activated protein kinases (MAPKs) signaling networks, interfacing the input (postsynaptic receptors) and the output (phosphorylation of proteins). A wide body of research has contributed to elucidating the role for MAPKs, such as ERK1/2, in memory, but less is known about the function of other MAPKs that are involved with fear memory such as the c-Jun N-terminal kinases (JNKs) that interact with the scaffold protein JNK-interacting proteins (JIPs). JIPs and JNKs have a variety of important functions in the brain that are not yet fully understood. Here, we studied the contribution of JIP1 to JNK-mediated learning and memory. Initial studies of excitotoxicity show that mice harboring mutations in the Jip1 gene that selectively blocks JIP1-mediated JNK activation results in the same phenotype as found for JNK3 isoform-deficient mice. As JNKs are involved in regulating fear memory, this raised the question as to whether such JIP1 mutants have the same changes in memory as that of carrying JNK deletion. We addressed this question by employing behavioral tests for spatial memory, contextual fear conditioning and electrophysiology. As seen with JNK-deficiency or with pharmacological inhibition of JNK in mice, mice with the Jip1 gene that selectively blocks JIP1-mediated JNK activation, displayed similar improvements in spatial memory, fear memory and plasticity. Furthermore, these mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. In addition, our studies with mice carrying mutation in JIP1 kinesin-1 binding domain, which normally facilitates the transport and assembly of JIP1/JNK signaling module to the neuronal processes, showed normal memory suggesting that that JIP1/JNK signaling is sufficient for the regulation of the NMDA receptor function independent of its cellular localization and the function as an adaptor between motor proteins and their