Calcineurin plays different roles in group II metabotropic glutamate receptor- and NMDA receptor-dependent long-term depression.

We investigated metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in hippocampal CA1 pyramidal neurons of 6- to 8-d-old [postnatal days 6-8 (P6-P8)] and 21- to 25-d-old (P21-P25) rats. In P6-P8 rats, induction of LTD depended on the activity of group II mGluRs. In P21-P25 rats, however, this LTD disappeared, and instead, NMDA receptor (NMDAR)-dependent LTD appeared. A bath containing a specific calcineurin (CaN) inhibitor restored the group II mGluR-dependent LTD in the neurons of the P21-P25 rats. Although postsynaptic injection of CaN inhibitors suppressed NMDAR-dependent LTD, it did not affect induction of group II mGluR-dependent LTD. These results demonstrate that CaN plays different roles in the induction of two forms of LTD: presynaptic CaN inhibits group II mGluR-dependent LTD, whereas postsynaptic CaN facilitates NMDAR-dependent LTD. These findings are the first demonstration in vitro of group II mGluR-dependent LTD that is negatively regulated by CaN via an age-dependent mechanism.

Vulnerability of synaptic plasticity in the complexin II knockout mouse to maternal deprivation stress.

The alterations in brain function and structure seen in schizophrenia are mediated by genetics as well as vulnerability due to environmental factors. Postmortem studies in schizophrenic patients have shown that expression of complexin II, which is involved in neurotransmitter release at central nervous system synapses, is decreased in the brain. We examined the physiological characteristics of complexin II gene-deficient mice subjected to maternal deprivation stress to determine whether psychological stress during the early stage of life affected the development of brain function. We compared the electrophysiological properties of CA1 hippocampal pyramidal neurons and spatial memory in the Morris water maze test in the wild-type mouse and the homozygous mutant. In the non-stressed mouse, no significant differences in transsynaptic responses and synaptic plasticity or spatial memory were seen, suggesting that complexin II does not play a critical role in transmitter release or synaptic plasticity under these conditions. In contrast, under conditions of maternal deprivation stress, the knockout mouse showed a significant decrease in post-tetanic potentiation and LTP induction and a significant impairment in Morris water Maze test compared to the wild-type mouse, suggesting that complexin II plays a significant role in neurotransmitter release and synaptic plasticity under this pathological condition. Taken together, these results show that mice lacking complexin II are vulnerable to maternal deprivation stress, which raises the possibility that the complexin II gene may be a factor in the onset of schizophrenia.

Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors.

The delta2 glutamate receptor (GluRdelta2) is predominantly expressed in the postsynaptic densities of parallel fiber-Purkinje cell synapses and plays a crucial role in cerebellar function. However, the mechanisms by which GluRdelta2 participates in cerebellar functions are largely unknown because GluRdelta2 does not bind glutamate analogs. We investigated the possibility that GluRdelta2 may be involved in channel formation together with other glutamate receptor families. We transiently expressed lurcher mutant AMPA receptor GluR1(Lc) and kainate receptor GluR6(Lc) in HEK293 cells. Cells expressing these constitutively active channels displayed a rectifying current-voltage (I-V) relationship. However, when cells were co-transfected with GluRdelta2(Lc), which had the arginine residue in the channel pore region, cells displayed a linear I-V relationship, a result that indicates GluRdelta2(Lc) formed functional heteromeric channels with GluR1(Lc) or GluR6(Lc). Assembly of GluRdelta2 with GluR1 or GluR6 was further confirmed by co-immunoprecipitation assays in HEK293 cells. In addition, GluRdelta2 receptors were partially co-immunoprecipitated from cerebellar synaptosomal fractions by antibodies against GluR2 or KA2. In contrast to lurcher channels, expression of wild-type GluRdelta2 significantly reduced the glutamate-induced current of the wild-type GluR1 receptors without affecting channel properties, such as current kinetics, dose-response relationship, and single-channel conductance. Thus, the heteromeric channel created by the association of wild-type GluR1 and GluRdelta2 may not be gated by glutamate and does not participate in glutamate-induced currents. These results suggest that GluRdelta2 and AMPA or kainate receptors can assemble to form heteromeric receptors in vitro and could modify glutamate signaling in vivo. These findings may help explain the role of GluRdelta2.

Imipramine, but not lithium, induces the serine/threonine phosphatase activity of calcineurin without affecting its mRNA expression in the rat brain.

The influence of imipramine and lithium on the expression of calcineurin (CaN) and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus was examined. Northern blot analysis demonstrated that single or repeated (14 day) administration of imipramine did not affect the levels of CaN A (catalytic subunit) mRNA in rat brain. Similarly, the administration of lithium for 1 or 14 days had no effect on the expression of CaN A mRNA. In contrast, the acute administration of imipramine significantly increased CaN activity in the cortex and hippocampus. In addition, the chronic (14 day) administration also significantly increased CaN activity. However, administration of lithium for either 1 or 14 days did not influence CaN activity. These findings indicate that imipramine, but not lithium, increases the phosphatase activity of CaN, suggesting that the changes in neuronal functions induced by CaN may be involved in the molecular activity of imipramine.

Redistribution of microtubules in dendrites of hippocampal CA1 neurons after tetanic stimulation during long-term potentiation.

It is now well accepted that the trafficking of AMPA receptors to the postsynaptic plasma membrane plays an essential role in long-term potentiation at the hippocampal Schaffer collateral synapses on CA1 pyramidal cells, but the motor mechanism of trafficking is unknown. We suspected that this trafficking of AMPA receptors during long-term potentiation may be carried out along microtubules by their motors. To ascertain this hypothesis, we light- and electron-microscopically studied the distribution of microtubules in dendrites of CA1 neurons of non-stimulated and stimulated rat hippocampal slices by using very strong tetanic stimulation for inducing long-term potentiation. As a result, we observed the following changes: 1. In immunofluorescence for microtubules and IP3 receptor using ultrathin-cryosections, linear signals of microtubules in main dendritic shafts were changed into fragmented. 2. Many spotty signals of microtubules emerged at the peripheral area of dendrites. Electron-microscopically, there was redistribution of microtubules in dendritic spines and dendritic shafts, and the thickening of post-synaptic density. 3. Many microtubules concentrated to thickened postsynaptic density in spines and new ones emerged, going to spines from dendritic shafts. These results strongly suggest that new tracks of microtubules from cell bodies to the stimulated postsynaptic membranes were produced after tetanic stimulation during long-term potentiation. This newly produced microtubules between stimulated postsynaptic membranes and the cell body must be the most promising candidate of the track for the trafficking of AMPA receptors to the stimulated postsynaptic plasma membrane.

Residential program for long-term hospitalized persons with mental illness in Japan: Randomized controlled trial.

Research on the merits of long-term group residences is inconclusive. The purpose of the present paper was to investigate the effects of supported group residence on the symptoms, social function, quality of life, general health quality, and the medical/psychiatric cost in Japan of a large number of psychiatric beds and long average length of stay. Patients were assessed every 6 months for 2 years using Positive and Negative Syndrome Scale, Katz Adjustment Scale, World Health Organization Quality of Life (WHO-QOL) and General Health Questionnaire 12-item version. Patients discharged to the supported group residence (SGR) significantly improved with regard to positive symptoms, the level of socially expected activities and free-time activities. The QOL physical domain of the inpatients was significantly more deteriorated compared to the SGR group. The total psychiatric/medical cost of the SGR group was approximately one-third that of the inpatient group, while the cost of the SGR to treat physical comorbidity was much higher. The present findings indicate that SGR has advantages for mental and social function but not for physical health. A major limitation of the present study was the high mean age (>60 years) of the subjects who had been hospitalized for a long period (mean, 24 years).