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Although platelet-derived growth factor (PDGF)-BB activates PDGF receptor-beta (PDGFR-beta) and, in turn, inhibits the glutamate N-methyl-D-aspartate (NMDA) receptor function, whether PDGF-BB modulates the CNS function mediated by another glutamate receptors, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, remains poorly understood. Here we now report the inhibitory effect of PDGF-BB on the AMPA receptor function in the nucleus tractus solitarius (NTS) by using slice patch-clamp techniques. Excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of the tractus solitarius in mouse NTS second-order neurons. EPSCs were nearly completely eliminated by CNQX but not by MK-801, implying mediation through non-NMDA receptors. PDGF-BB significantly decreased the amplitude of EPSCs without affecting the mean decay time constant. This inhibitory effect was transient and reversible after removing PDGF-BB. Furthermore, PDGF-BB significantly reduced the amplitude of AMPA-induced currents in NTS neurons, which showed that PDGF-BB could suppress the AMPA receptor-mediated excitatory input via the postsynaptic mechanism. The inhibitory effect of PDGF-BB on EPSCs was not observed in mutant mice with conditional deletion of the PDGFR-beta gene in neurons. Together, these studies suggest that the PDGF-B/PDGFR-beta axis inhibits the AMPA receptor-mediated synaptic transmission that comprises the major part of the primary afferent to the NTS second-order neuron. The detected inhibitory action may be involved in the CNS regulation of the respiratory response.

We examined the correlation between seizure activity and development of mossy fiber sprouting in the hippocampal formation using Timm staining in a newly developed Ihara epileptic rat (IER). The sprouting of mossy fibers were clearly shown in the inner molecular portion of the dentate gyrus and in the stratum oriens of CA3 pyramidal cell layer with repeated seizures. A positive correlation between the frequency of generalized tonic and clonic convulsions and the Timm staining score in molecular layer of dentate gyrus was revealed. Sprouting of mossy fiber in IER seems to be linked with seizure activities resulting from epileptic bursts, not to the genetic mutation.

The neuronal expression of mRNA of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was investigated in immature rat brains. Two rat models were used in this study. One was a hypoxic/ischemic (HI) brain injury model, and the other was an N-methyl-d-aspartate (NMDA) intracerebral injection model. The former model was made by permanent ligation of the left carotid artery and subsequent exposure to 2 h of hypoxia. After the HI insult, the HB-EGF mRNA was assessed by a Northern blot analysis. The levels of transcripts for HB-EGF in the cerebral cortex and the hippocampus of the ligated side were significantly higher than those of non-treated rats from 3 to 24 h after the insult. The spatial distribution of the mRNA of HB-EGF was also studied using in situ hybridization. Three to 24 h after the hypoxia, hybridization signals were intense in neuronal cytoplasm on the ligated side, but a focally decreased signal was seen in infarcted areas. Strongly increased mRNA expression was observed in the neurons surrounding the infarct. These results indicate that a neonatal HI insult induces a neuronal upregulation of HB-EGF immediately after hypoxia. In the latter model, the intracerebral NMDA injection also induced an immediate, strong upregulation of HB-EGF transcripts. Our results indicate that HB-EGF may act as a neuroprotective factor in the immature brain with HI injury by modulating the neurotoxic process which is mediated by overactivation of the NMDA receptor.

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells and glial cells. For a better understanding of the role of PDGF B-chain in the brain, the expression of PDGF B-chain was examined immunohistochemically in penetrating injury to the rat brain. Shrunken neurons were distributed with enhanced PDGF B-chain-related immunoreactivity (PBRI) in the vicinity of the lesion during a period from day 1 to day 4 post injury. Platelet-derived growth factor B-chain-related immunoreactivity was transiently observed also in the cytoplasm of the numerous brain macrophages in the lesion on day 3 and day 4. These distributions of PBRI in the lesion were closely related to the neovascularization and astrogliosis there. The close time and spatial correlation between the expression of PBRI and cellular responses to injury seen in this study suggests PDGF B-chain has an important role in the healing process of cerebral wound.

According to a recent report, messenger RNA coding for a member of the epidermal growth factor (EGF) family, heparin-binding EGF-like growth factor (HB-EGF), is expressed in the central nervous system (CNS). To obtain information about the role of HB-EGF in the brain, we carried out Northern analysis, in situ hybridization, and immunohistochemical studies evaluating the distribution and amounts of the growth factor using cDNA HB-EGF probes and an antibody raised against synthetic HB-EGF propeptide. Northern analysis revealed transcripts for HB-EGF in all regions of normal rat brain. Immunohistochemically, HB-EGF was demonstrated extensively in neurons at levels varying according to location. HB-EGF mRNA also was detected in neurons, suggesting that the growth factor is produced in these cells. HB-EGF mRNA and immunoreactivity were also demonstrated in interfascicular oligodendrocytes. These findings suggest that HB-EGF is a physiologic ligand for brain EGF receptors, and is likely to be important in neural function.

In an attempt to clarify the relationship between ecto-5′-nucleotidase (5′-N) activity and cell differentiation of glial cells, dibutyryl cyclic AMP (dBcAMP), which induces cell differentiation, was administrated to cultured rat glioma cells in logarithmic and confluent phases of cultivation. To evaluate the cellular differentiation, cell morphology and the number of glial fibrillary acidic protein (GFAP) positive cells were examined. Treatment with 1 mM dBcAMP decreased cell proliferation and induced cell differentiation in both the logarithmic and the confluent phases. The number of GFAP-positive cells increased with cellular aging and this tendency was enhanced by dBcAMP administration. Ecto-5′-N activity was higher in dBcAMP treated cells than in non-treated cells in both the logarithmic and the confluent phases. These findings suggest that ecto-5′-N activity of C6 glioma cells is increased by dBcAMP actions and is accompanied by cell differentiation.