Role of the group III metabotropic glutamate receptor in LTP, depotentiation and LTD in dentate gyrus of freely moving rats.

We investigated whether group III metabotropic glutamate (mGlu) receptors are critically involved in the expression of long-term potentiation (LTP), depotentiation, or long-term depression (LTD) in the dentate gyrus of freely moving rats. Male Wistar rats (7 8 weeks) underwent implantation of stimulating and recording electrodes in the medial perforant path and dentate gyrus granule cell layer, respectively. A cannula was permanently implanted into the ipsilateral cerebral ventricle to enable drug administration. Intracerebral injection of the group III mGlu receptor agonist, L(+)-2-amino-4-phosphonobutanoic acid (AP4), significantly inhibited LTP at a concentration which unaffects basal synaptic transmission. Depotentiation. short-term depression (STD) and LTDwere unaffected by the agonist. The antagonist. (R.S)-r-cyclopropyl-4-phosphonophenylglycine (CPPG), inhibited agonist effects. but had no independent effects on basal synaptic transmission. CPPG did not affect the profile of LTP, depotentiation or STD elicited by low frequency stimulation (LFS) at 0.5 or 3 Hz. but significantly impaired LTD expression (at I Hz) and STD elicited at 5 Hz. These findings suggest that activation of group III mGlu receptors is critically required for LTD. but not LTP or depotentiation in the dentate gyrus and provide evidence for the involvement of separate mechanisms underlying LTD and depotentiation.

An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats.

The involvement of metabotropic glutamate (mGlu) receptors in the induction of long-term potentiation (LTP) in vivo has been consistently documented. We have investigated whether LTP induction in the dentate gyrus of rats leads to changes in expression of mGlu2/3 or -5 receptor subtypes in the hippocampus. LTP was induced at the medial perforant path-dentate gyrus synapses, and mGlu receptor expression was examined by Western blot or in situ hybridization. An up-regulation of mGlu5 receptors was observed in the hippocampus both 24 and 48 h following LTP induction. This effect was restricted to the dentate gyrus and CA1 region, whereas no changes in mGlu5 receptor protein (but an increase in mRNA levels) were observed in the CA3 region. The increased expression of mGlu5 receptors was directly related to the induction of LTP, because it was not observed when tetanic stimulation was carried out in animals treated with the NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5). Western blot analysis also showed a reduced expression of mGlu2/3 receptors in the whole hippocampus 24 h after LTP induction, indicating that the increased expression of mGlu5 receptors was specific. These data suggest that an up-regulation of mGlu5 receptors is a component of the plastic changes that follow the induction of LTP at the perforant path-dentate gyrus synapse.

Tissue plasminogen activator as a key effector in neurobiology and neuropathology.

Tissue plasminogen activator (tPA) is expressed by many types of neurons in the developing and adult rodent brain. We have now mapped tPA transcripts and protein in the human central nervous system using tissue arrays and find widespread expression, in particular in neocortical mantle, thalamus, amygdala, and hippocampal pyramidal neurons. The abundant presence of tPA protein in cellular vesicles implies that its acute release, e.g. upon ischaemic stroke or trauma, could play a role in neuronal damage. We also found in patients with multiple sclerosis (MS), and to a lesser extent patients with leukaemia and encephalitis, prominently elevated tPA activity in the cerebrospinal fluid and in MS in neurons in the proximity of areas of demyelination elevated tPA mRNA and antigen levels. In addition, we observed up-regulation of tPA expression in a mouse model of MS, experimental autoimmune encephalomyelitis. Accumulating evidence implies roles for tPA in normal neural function, as well as in neurodestructive processes in humans, such as occur in MS and brain tumours and warrant further studies on expression of tPA and its regulatory molecules in neurodegenerative diseases.

Survival of patients with primary CNS tumours in Estonia.

We studied a population-based survey that included 1417 patients with a primary central nervous system (CNS) tumour diagnosed in Estonia between 1986 and 1996. Survival rates at 1 and 5 years and median survival by histology and patient's age at diagnosis were estimated. Median survival time for all tumours was 33.2 months and 1- and 5-year survival rates were 59.3 and 46.0%, respectively. In multivariate analysis, younger age, better clinical condition (i.e. a Karnofsky Performance Status (KPS) score of 60 and more) and tumour histology were all dependent prognostic factors for better survival. Risk of death was more than 8 times greater for glioblastoma (Risk Ratio (RR) 8.31) and approximately seven times greater for anaplastic astrocytoma (RR 7.22) and other gliomas (RR 5.74) compared with meningiomas. Comparing the first (1986-1989) and the third (1994-1996) time periods, statistically significant improvements in survival occurred for all tumours and astrocytomas. Declines in survival during the second period (1990-1993) were statistically significant for all the tumour groups, but the most striking decrease took place in patients with glioblastoma. Age-specific rates showed that the increase in survival was more evident for patients aged between 45 and 64 years.

Comparative expression analysis of the genes encoding polypyrimidine tract binding protein (PTB) and its neural homologue (brPTB) in prenatal and postnatal mouse brain.

The polypyrimidine tract binding protein (PTB) and its recently discovered homologue brain-enriched PTB (brPTB) are RNA binding proteins involved in the control of alternative splicing. We have characterized expression patterns of the PTB and brPTB in course of mouse brain development, using mRNA in situ hybridization. PTB is expressed in choroid plexi and ependyma at all the stages of development and temporarily in the mantle layer of migrating neuroblasts of fore-, mid- and hindbrain and in the external granular layer of cerebellum. In the neurons of adult mouse cerebrum and cerebellum expression of PTB is undetectable. In contrast to this, brPTB is expressed ubiquitously in neuroblasts of various parts of embryonic brain and in the differentiated neurons of postnatal cerebrum and cerebellum. brPTB mRNA is not observed in choroid plexi and ependymal layer. Thus, in the embryonic brain expression patterns of PTB and brPTB overlap, but in the course of brain development the patterns become complementary to each other.

Requirement of translation but not transcription for the maintenance of long-term depression in the CA1 region of freely moving rats.

Hippocampal long-term depression (LTD) comprises a persistent reduction in synaptic strength that can be induced in the CA1 region by repeated low-frequency stimulation (LFS). Previous studies have demonstrated that hippocampal long-term potentiation requires de novo protein synthesis. Whether hippocampal LTD is also protein synthesis-dependent is not known. In this study, we investigated if the previous administration of translation inhibitors (anisomycin or emetine) or a transcription inhibitor (actinomycin-D) influenced the profile of LTD in freely moving adult Wistar rats. Seven- to 8-week-old animals underwent chronic implantation of a recording electrode in the CA1 stratum radiatum and a stimulation electrode in the Schaffer collateral/commissural fiber pathway. A cannula was implanted in the ipsilateral cerebral ventricle to enable drug administration. Experiments were commenced 10 d after the implantation procedure. Immediately after application of LFS (1 Hz, 900 pulses) robust LTD was seen that persisted for >8 hr in control animals. Application of anisomycin (240 microg/5 microl) emetine (240 microg/5 microl) before LFS prevented the expression of LTD or approximately 4.5 hr after LFS. Previous administration of actinomycin D (72 microg/12 microl) had no effect on the expression of LTD. None of the compounds elicited significant effects on basal synaptic transmission when administered in the absence of LFS. These data suggest that LTD in the CA1 region in vivo is protein synthesis-dependent. Furthermore, persistent LTD can be established through the translation of existing mRNA, whereas de novo mRNA transcription does not appear to be necessary.

Epidemiology of primary central nervous system tumors in Estonia.

During the period from 1986 to 1996, 1,665 cases of primary central nervous system (CNS) tumors were identified in the resident population of Estonia. Histological verification was available in 81% of the cases. Gliomas were more common in men, while meningiomas and neurinomas were more common in women. No significant difference was observed between the sexes for all primary CNS tumors. The age-specific incidence increased from the age of 30, reached a maximum in the age range of 50-69 years and declined in the elderly which may reflect under-diagnosis. The age-adjusted incidence rate for CNS tumors was 8.5/100,000 population. A comparison of our results with those of a previous study carried out in Estonia revealed a significant histology-specific increase in incidence in all age groups.

Depotentiation in the dentate gyrus of freely moving rats is modulated by D1/D5 dopamine receptors.

Hippocampal depotentiation comprises a reversal of tetanization- induced long-term potentiation (LTP) which occurs following low-frequency stimulation. In the CA1 region, it has been reported that agonist activation of D1/D5 dopamine receptors enhances LTP expression and inhibits depotentiation. The role of these receptors in synaptic plasticity in the dentate gyrus (DG) has not been characterized. This study therefore investigated the role of D1/D5 receptors in LTP and depotentiation in the DG of freely moving rats. Male Wistar rats underwent chronic implantation of a recording electrode in the DG granule cell layer, a bipolar stimulating electrode in the medial perforant path and a cannula in the ipsilateral cerebral ventricle (to enable drug administration). The D1/D5 agonist Chloro-PB dose-dependently inhibited depotentation in the DG. This effect was prevented by the D1/D5 antagonist SCH 23390. Neither D1/D5 agonist nor antagonist had an effect on LTP expression or basal synaptic transmission. These results highlight differences between D1/D5 receptor-involvement in LTP and depotentiation in the CA1 region and DG, and indicate that whereas D1/D5 receptor activation may not be a critical factor in LTP induction in the DG, a differential role for these receptors in the expression of depotentiation, in this hippocampal subfield, may exist.

Tenascin expression patterns and cells of monocyte lineage: relationship in human gliomas.

Stromal extracellular matrix (ECM) components are thought to play an important role in regulating invasion of human gliomas. Macrophages and microglial cells may heavily influence the integrity of the extracellular compartment of gliomas, and the affected ECM may play a key role in regulating migratory activity of both tumor cells and macrophages/microglia. The aim of this investigation was to study immunohistochemically the expression patterns of four ECM components: fibronectin, laminin, collagen IV, and tenascin (TN) in human gliomas, with special attention to TN. Our main goal was to study the possible correlation between TN expression and macrophagic/microglial infiltration in gliomas. Altogether, 90 gliomas were studied. Tumors included 46 glioblastomas, 19 anaplastic gliomas, 22 low grade gliomas, and 3 pilocytic astrocytomas. Vascular TN prevailed in perinecrotic areas of glioblastomas, whereas interstitial TN was more often expressed distant from necrosis and in the ECM of anaplastic and low grade gliomas. Double staining with CD68 and anti-TN antibodies showed that macrophagic/microglial density was significantly higher in TN-positive areas of most of the glioblastomas and anaplastic gliomas, whereas microglial percentage from total number of CD68-positive cells was in most of the cases significantly higher in TN-negative areas. In addition, we saw a morphologically spatial correlation between higher densities of macrophagic/microglial infiltration and TN expression in perinecrotic areas in glioblastomas. Attachment of macrophages to TN-positive basement membrane zones of newly formed stromal blood vessels was evident. On the basis of our results, we conclude that TN may play a crucial role in regulating trafficking of cells of monocyte lineage in human gliomas.

Time-dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors.

Depotentiation comprises a reversal of tetanization-induced long-term potentiation (LTP) which occurs following low-frequency stimulation (LFS) in the hippocampus in vivo. Although depotentiation has been consistently demonstrated in the CA1 region, no positive reports of the existence of depotentiation in the dentate gyrus in vivo have occurred. This study therefore investigated whether depotentiation is possible in the dentate gyrus in vivo. We found that depotentiation can be induced, but it is very tightly dependent on the interval between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization produced significant depotentiation, whereas LFS given 10-30 min following tetanization had no significant effect on the expression of LTP. Depotentiation occurred in two phases: a transient depression of evoked responses to below pre-tetanization values, which occurred in the first 60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic glutamate receptors (mGluRs) play an important role in the expression of long-term depression in vivo. We therefore investigated whether group 2 mGluRs contribute to depotentiation. The group 2 antagonist (2S)-alpha-ethylglutamic acid (EGLU) inhibited the early transient depression at a concentration which inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU also inhibited the transient depression induced by 5 Hz given alone. Increasing the concentration of EGLU prevented depotentiation, however. The group 2 agonist (S)-4-carboxy-3-hydroxyphenyl- glycine (4C3HPG) inhibited LTP and enhanced depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.