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Tumor necrosis factor-␣ (TNF-␣

Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

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Activity-dependent plastic changes in the strength

The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.Long-term potentiation (LTP) in the hippocampus is an activity-dependent modification of synaptic strength and considered a potential cellular mechanism underlying learning and memory (Bliss and Collingridge 1993). Brain-derived neurotrophic factor (BDNF) is implicated in synaptic plasticity such as LTP (Barde et al. 1982;Leibrock et al. 1989;Patterson et al. 1992;Figurov et al. 1996). Recently, we have demonstrated that BDNF mRNA in the hippocampus increased after a radial maze training, and treatment with an antisense BDNF oligonucleotide led to impairment of not only the acquisition, but also the maintenance and/or recall of spatial memory (Mizuno et al. 2000). Although these findings imply an essential role for BDNF in spatial learning and memory, the molecular mechanisms by which BDNF regulates spatial memory processes remain to be determined .N-Methyl-D-aspartate (NMDA) receptors are heteromeric glutamate-gated ion channels in the central nervous system, which are constructed by two families of an essential subunit NR1 and other subunits NR2A-D (Hollmann and Heinemann 1994), and are involved in synaptic plasticity (Collingridge 1987). Activation of NMDA receptors generates LTP, whereas inhibition and deletion of NMDA receptors impair LTP and spatial learning and memory (Morris et al. 1986;Sakimura et al. 1995;Tsien et al. 1996). NMDA receptor activity is modulated by the phosphorylation catalyzed by several protein kinases including protein kinase A, protein kinase C, and calcium/calmodulin-dependent protein kinase II (Omkumar et al. 1996;Tingley et al. 1997;Gardoni et al. 1999).Phosphorylation at tyrosine residues leads to an increase in NMDA current (Chen and Leonard 1996). Compelling evidence has been provided that NMDA receptors are substrates of protein tyrosine kinases. Fyn is a nonreceptor Src-family tyrosine kinase expressed abund...

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