Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus.

The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.

Dendritic mRNA targeting of Jacob and N-methyl-d-aspartate-induced nuclear translocation after calpain-mediated proteolysis.

Jacob is a recently identified plasticity-related protein that couples N-methyl-d-aspartate receptor activity to nuclear gene expression. An expression analysis by Northern blot and in situ hybridization shows that Jacob is almost exclusively present in brain, in particular in the cortex and the limbic system. Alternative splicing gives rise to multiple mRNA variants, all of which exhibit a prominent dendritic localization in the hippocampus. Functional analysis in primary hippocampal neurons revealed that a predominant cis-acting dendritic targeting element in the 3'-untranslated region of Jacob mRNAs is responsible for dendritic mRNA localization. In the mouse brain, Jacob transcripts are associated with both the fragile X mental retardation protein, a well described trans-acting factor regulating dendritic mRNA targeting and translation, and the kinesin family member 5C motor complex, which is known to mediate dendritic mRNA transport. Jacob is susceptible to rapid protein degradation in a Ca(2+)- and Calpain-dependent manner, and Calpain-mediated clipping of the myristoylated N terminus of Jacob is required for its nuclear translocation after N-methyl-d-aspartate receptor activation. Our data suggest that local synthesis in dendrites may be necessary to replenish dendritic Jacob pools after truncation of the N-terminal membrane anchor and concomitant translocation of Jacob to the nucleus.

Altered postsynaptic-density-levels of caldendrin in the para-chloroamphetamine-induced serotonin syndrome but not in the rat ketamine model of psychosis.

Caldendrin is a synaptic calcium sensor protein that is tightly associated with the postsynaptic density (PSD). Previous work has shown that the association of the protein with the synapse is highly dynamic and is increased in an activity-dependent manner. In the present study the caldendrin-association with the postsynaptic cytomatrix was analyzed in animal models of psychosis and drug abuse induced neurotoxicity. Subchronic administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist ketamine, serving as a model of NMDA-receptor hypofunction and schizophrenia showed no significant effect on the PSD-levels of caldendrin, indicating that NMDA-receptor activity is not required to keep caldendrin at the synapse. However, administration of high doses of the serotonergic neurotoxin p-chloroamphetamine (PCA) lead to significant changes in the association of caldendrin with the PSD. These results underscore the dynamic association of caldendrin with the PSD and suggest a role of this synaptic calcium sensor in the PCA-induced serotonin syndrome.

A reduced number of cortical neurons show increased Caldendrin protein levels in chronic schizophrenia.

Caldendrin is a neuronal calcium sensor protein that is tightly associated with the postsynaptic density (PSD) of excitatory synapses. It has an established role in synapto-dendritic Ca(2+)-signaling as a multifunctional regulator of intracellular Ca(2+) levels. Previous work has shown that expression levels of protein components involved in signaling processes at excitatory synapses are significantly altered in the brains of schizophrenic patients. Furthermore, it is widely accepted that synaptic pathology associated with the glutamatergic N-methyl-d-aspartate (NMDA) receptor is a feature of the disease. Here we report that in postmortem brains of chronic schizophrenics (N: 12) as compared to age-and sex-matched controls (N: 12) the number of Caldendrin-immunoreactive neurons are significantly reduced in the left dorsolateral prefrontal cortex, a brain region prominently associated with schizophrenia. Less dramatic changes were observed in other cortical regions. However, despite the reduced number of immunoreactive neurons, absolute Caldendrin protein levels were elevated and no change in Caldendrin PSD-levels were observed as compared to the left dorsolateral prefrontal cortex in the normal human brain. Thus, synapto-dendritic Ca(2+)-signaling via Caldendrin is altered in schizophrenic patients by a redistribution of the protein into a lower number of pyramidal neurons, which express higher Caldendrin levels. Since Caldendrin is a multivalent regulator of voltage dependent Ca(2+)-channels and Ca(2+)-release channels the loss of Caldendrin mediated synapto-dendritic Ca(2+)-signaling processes in some neurons together with its concurrent upregulation in others should profoundly change their synapto-dendritic Ca(2+)-signaling. These observations add to existing evidence for a de-regulation of neuronal Ca(2+)-signaling in schizophrenia.