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Biomedical subjects

B J Morris

Publications and source records attributed to B J Morris.

At least 19 recordsLinked to original sources
PubMed2006

Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs.

The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The levels of the mRNAs encoding TNF, IL-2, IL-6, TGF 1, 2, 3, IL-3 and GM-CSF were measured in the prefrontal cortex, cortex, hippocampus, ventral and dorsal striatum regions of male hooded Long Evans rats after acute drug administration. Antipsychotic drugs and PCP significantly reduced the levels of TNF in the prefrontal cortex compared to vehicle-treated animals, whilst other cytokines remained unchanged. In addition, significant reductions in the levels of TNF mRNA in the prefrontal cortex still occurred 24h after acute PCP administration. However, levels of TNF mRNA were restored to control values after chronic PCP treatment, whereas increased expression was detected in animals co-administered with haloperidol. Levels of TNF mRNA were also found to be significantly increased in the prefrontal cortex of schizophrenic subjects. The relationship between TNF levels and schizophrenia are discussed.

Adult↗
PubMed2005

Divergent regulation of Pyk2/CAKbeta phosphorylation by Ca2+ and cAMP in the hippocampus.

Proline-rich tyrosine kinase 2 (Pyk2) is activated in neurones following NMDA receptor stimulation via PKC. Pyk2 is involved in hippocampal LTP and acts to potentiate NMDA receptor function. Elevations of intracellular Ca2+ and cAMP levels are key NMDA receptor-dependent triggering events leading to induction of hippocampal LTP. In this study, we compared the ability of A23187 (Ca2+ ionophore) or forskolin (adenylate cyclase activator) to modulate the phosphorylation of Pyk2 in rat hippocampal slices. Using an immunoprecipitation assay, phosphorylated Pyk2 levels were increased following treatment with A23187, levels peaking at around 10 min. Staurosporine, at concentrations inhibiting conventional and novel isoforms of PKC, and chelerythrine, at concentrations inhibiting the atypical PKC isoform PKMxi, were compared for their ability to attenuate the effect of A23187. Exposure of acute hippocampal slices to either chelerythrine or staurosporine completely blocked enhanced phosphorylation of Pyk2 by A23187, suggesting a possible involvement of PKMxi and typical PKCs in Pyk2 activation by Ca2+. In contrast, application of forskolin reduced phosphorylated Pyk2 below basal levels, suggesting that cAMP inhibits Pyk2. These results implicate Ca2+ and multiple forms of PKC in the activation of Pyk2 downstream of NMDA receptors and suggest that cAMP-dependent processes exert a suppressive action on Pyk2.

Alkaloids↗
PubMed2004

N-methyl-D-aspartate and brain-derived neurotrophic factor induce distinct profiles of extracellular signal-regulated kinase, mitogen- and stress-activated kinase, and ribosomal s6 kinase phosphorylation in cortical neurons.

Stimulation of N-methyl-D-aspartate (NMDA) receptors is believed to underlie long-term memory formation, and excessive NMDA receptor activation has been linked to several neuropathological conditions. Phosphorylation and activation of p42/44 mitogen-activated protein kinase (ERK) is believed to mediate many of these effects, but the downstream targets of ERK in response to NMDA activation have not been determined. In primary cultures of rat cortical neurons, we found that NMDA was able to elevate phosphorylation of mitogen- and stress-activated kinase 1 (MSK1) as well as ERK. Likewise, brain-derived neurotrophic factor (BDNF) treatment increased phosphorylation of MSK1 and ERKs. The NMDA-induced MSK1 phosphorylation was sensitive to the MEK inhibitor 2'-amino-3'-methoxyflavone (PD98059) and the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). MSK1 activation by NMDA was transient, although ERK remained phosphorylated within the neuronal cytoplasm for several hours. Although BDNF increased ribosomal S6 kinase (RSK) phosphorylation, NMDA had no discernable effect on the phosphorylation of RSKs. Thus, phosphorylation and activation of MSK1 but not RSK could be an important step in the pathway linking NMDA-induced ERK phosphorylation to the activation of transcription factors required for the formation of long-term memory.

Animals↗
PubMed2004

Regulation of myosin light chain phosphorylation by RhoB in neuronal cells.

The phosphorylation of myosin light chain (MLC) is a key regulatory point in the control of cellular morphology. Evidence suggests that RhoA-a member of the Rho GTPase family-regulates MLC phosphorylation via Rho kinase (ROK). Neurones display subtle alterations in their cytoarchitecture during the synaptic plasticity following high-frequency stimulation. We have recently demonstrated that RhoB, and not RhoA, is activated in neurones by high-frequency stimulation. However, the downstream consequences of RhoB activation in cells are unclear. In this study, we tested the hypothesis that RhoB might stimulate neuronal MLC phosphorylation. Transfection of PC12 cells with constitutively active RhoB increased MLC phosphorylation. Conversely, dominant-negative RhoB vectors reduced MLC phosphorylation. The effect of RhoB was attenuated by pretreatment with a selective ROK inhibitor. This confirms that Rho GTPases are important regulators of MLC phosphorylation, but suggests that, in neuronal cells, the control is exerted via RhoB rather than RhoA.

Action Potentials↗
PubMed2004

Differential regulation of MAP2 and alphaCamKII expression in hippocampal neurones by forskolin and calcium ionophore treatment.

The genes encoding microtubule-associated protein 2 (MAP2), and the alpha subunit of calcium/calmodulin-dependent protein kinase II (alphaCaMKII), are members of a small number of genes whose expression is increased in hippocampal neurones during the intermediate phase of long-term potentiation (LTP)-a phase dependent on mRNA translation but not on gene transcription. However, the intracellular signalling pathways which mediate these increases in expression are largely unknown. Organotypic slice cultures of rat hippocampus were exposed to either forskolin (to elevate cAMP levels), A23187 (to increase intracellular Ca(2+) levels) or the corresponding vehicle. The levels of immunoreactive (ir-) MAP2 were increased 4 h after forskolin treatment, but were unaffected by A23187 treatment. Conversely, the levels of ir-alphaCaMKII were increased 4 h after A23187 treatment, but were unaffected by forskolin. The regulation of the expression of these proteins was the same in the CA3 region as in the CA1 and dentate gyrus of the hippocampus. While rapamycin reduced the basal levels of ir-MAP2, it did not affect the ability of either forskolin or A23187 to enhance ir-MAP2 or ir-alphaCaMKII levels. These results suggest that cAMP and Ca(2+) differentially modulate the expression of these two plasticity-related genes, and that translational enhancement via the mammalian target of rapamycin kinase is not involved in these effects.

Animals↗
PubMed2004

Increased long-term potentiation in the CA1 region of rat hippocampus via modulation of GTPase signalling or inhibition of Rho kinase.

There is accumulating evidence that Ras, and Ras-related GTPases of the Rho family, such as RhoA, RhoB and Rac1, are involved in synaptic plasticity in brain regions such as the hippocampus. We have recently shown that Rho family GTPases are activated by synaptic transmission in the CA1 region of the hippocampus. Since the function of these GTPases is dependent on post-translational isoprenylation by either farnesyl or geranylgeranyl transferases, we tested the hypothesis that inhibition of isoprenylation would modify long-term potentiation (LTP). Farnesyl transferase inhibition, which suppressed activation of RhoB and Ras but not RhoA or Rac1, reduced the magnitude of LTP, while geranylgeranyl transferase inhibition, which inhibited RhoA and Rac1 but not RhoB, increased the magnitude of LTP. In addition, Y-27632, a specific inhibitor of a downstream effector of Rho GTPases-Rho-kinase-also increased the magnitude of LTP. This provides strong evidence that GTPases are important mediators of synaptic plasticity, and demonstrates that Rho-kinase acts to reduce the degree of plasticity at hippocampal synapses during LTP. Rho-kinase inhibitors have the unusual property of increasing the magnitude of LTP, and so may be potential cognitive enhancers.

Animals↗
PubMed2004

cAMP controls human renin mRNA stability via specific RNA-binding proteins.

It is now recognized that post-transcriptional mechanisms are pivotal to renin production. These involve factors that modulate renin mRNA stability. In 2003 new data has emerged from work in Australia and Germany that has identified several of the, as many as, 20 or so proteins involved. These include CP1 (hnRNP E1), HuR, HADHB, dynamin, nucleolin, YP-1, hnRNP K and MINT-homologous protein. Cyclic AMP (cAMP) is a crucial regulator of renin secretion as well as transcriptional and post-transcriptional control of expression. Many of the RNA-binding proteins that were identified responded to forskolin, increasing in amount by two to 10-fold. The cAMP mechanisms that regulate renin mRNA target, at least in large part, other genes that presumably encode some of these proteins. The increase in the expression of these then facilitates, sequentially, renin mRNA stabilization and destabilization. Our data, using a battery of different techniques, confirm that CP1 and HuR stabilize renin mRNA, whereas HADHB causes destabilization. These proteins target cis-acting C-rich sequences (in the case of CP1) and AU-rich sequences (HuR) in the distal region of the 3'-untranslated region of renin mRNA. We found HADHB was enriched in juxtaglomerular cells and that that within Calu-6 cells HADHB, HuR and CP1 all localized in nuclear subregions, as well as cytoplasm (HADHB and CP1) and mitochondria (HADHB) commensurate with the role each plays in control of renin mRNA stability. The specific proteins that bind to human renin mRNA have begun to be revealed. Cyclic AMP upregulates the binding of several of these proteins, which in turn affect renin mRNA stability and thus overall expression of renin.

Cyclic AMP↗
PubMed2003

Distribution of Rho family GTPases in the adult rat hippocampus and cerebellum.

Small GTPases are monomeric guanine nucleotide binding proteins of 20-25 kDa mass. Rho GTPases belong to the Ras superfamily of small GTPases. The small GTPases of the Rho family have been shown to participate in the organisation of the actin cytoskeleton and signal transduction pathways leading to gene transcription. Recent evidence suggests that Rho family GTPases may play an important role in synaptic communication in the brain, and particularly in synatic plasticity. In this study the distribution of RhoA, RhoB, RhoG, Cdc42, and Rac1 was investigated in hippocampal and cerebellar tissue of adult rat brain using immunohistochemical techniques. Previous studies suggest that distribution of Rho family mRNA is uniform throughout these structures. Here we provide evidence for differences in expression of these proteins between different regions of the hippocampus, and between the molecular and granular layers in the cerebellum. These differences may prove important with regard to the physiological functions of Rho family GTPases.

Age Factors↗
PubMed2003

Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension.

In a study of the genetic basis of essential hypertension (HT), we tested four variants in three candidate genes not previously investigated in HT. These encoded the endothelin receptor type A (EDNRA), which transduces most of the vasoconstrictive properties of endothelin-1, protein kinase lysine deficient 4 (WNK4) whose gene resides in a HT linkage region on chromosome 17, and FK506-binding protein 1B (FKBP1B), which can reduce blood pressure by increasing nitric oxide. The variants were: for EDNRA, a G-->A in the 5'-UTR and C-->T in exon 8; for WNK4, a tetranucleotide repeat in intron 10; and for FKBP1B, a T-->C in exon 4. Subjects were Anglo-Celtic white Australians and included 155 HTs with two HT parents and 245 normotensives (NTs) whose parents were both NT. For EDNRA, we found a weak association of the exon 8 variant with HT (p = 0.019) and association of the 5'-UTR variant with elevation in systolic and diastolic blood pressure (BP) (p = 0.038 and 0.0031, respectively). The WNK4 intron 10 variant and the FKP1B exon 4 variant showed no association with HT, but tracking with BP was seen for the latter (p = 0.015 and 0.0011 for systolic and diastolic BP, respectively). Our study thus suggests possible involvement of EDNRA in essential HT.

5' Untranslated Regions↗
PubMed2003

Striatal neurones show sustained recovery from severe hypoglycaemic insult.

Glucose deprivation provides a reliable model to investigate cellular responses to metabolic dysfunction, and is reportedly associated with permanent cell death in many paradigms. Consistent with previous studies, primary cultures of rat striatal neurones exposed to 24-h hypoglycaemia showed dramatically decreased sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) metabolism (used as a marker of cell viability) and increased TUNEL staining, suggesting widespread DNA damage typical of apoptotic cell death. Remarkably, restoration of normal glucose levels initiated a sustained recovery in XTT staining, along with a concomitant decrease in TUNEL staining, even after 24 h of hypoglycaemia, suggesting recovery of damaged neurones and repair of nicked DNA. No alterations in the levels of four DNA repair proteins could be detected during hypoglycaemia or recovery. A reduction in intracellular calcium concentration was seen in recovered cells. These data suggest that striatal cells do not die after extended periods of glucose deprivation, but survive in a form of suspended animation, with sufficient energy to maintain membrane potential.

Animals↗
PubMed2003

Activation of Rho GTPases by synaptic transmission in the hippocampus.

Ras-related GTPases of the Rho family, such as RhoA and RhoB, are well-characterised mediators of morphological change in peripheral tissues via their effects on the actin cytoskeleton. We tested the hypothesis that Rho family GTPases are involved in synaptic transmission in the CA1 region of the hippocampus. We show that GTPases are activated by synaptic transmission. RhoA and RhoB were activated by low frequency stimulation, while the induction of long-term potentiation (LTP) by high frequency stimulation was associated with specific activation of RhoB via NMDA receptor stimulation. This illustrates that these GTPases are potential mediators of synaptic transmission in the hippocampus, and raises the possibility that RhoB may play a role in plasticity at hippocampal synapses during LTP.

Animals↗
PubMed2002

Involvement of NMDA receptors and a p21Ras-like guanosine triphosphatase in the constitutive activation of nuclear factor-kappa-B in cortical neurons.

The transcription factor nuclear factor-kappa-B (NF-kappaB) is now recognised as a key mediator of physiological and pathological plasticity in the central nervous system (CNS), and ionotropic glutamate receptor stimulation potently triggers NF-kappaB activation. This study was designed to identify the mechanisms responsible for the high basal levels of activated NF-kappaB present in neurons in the cerebral cortex. In cultured cortical neurons, the basal levels of activated NF-kappaB were reduced by the glutamate receptor antagonists MK801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but were not affected by exposure to a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor, a p38 MAP kinase inhibitor or a cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor. However, activated NF-kappaB levels were reduced by a guanylate cyclase inhibitor, the Src-family tyrosine kinase inhibitor PP1, or the farnesyl transferase inhibitors manumycin and farnesyl transferase (Ftase) inhibitor 1. There was no additive effect when MK801 was applied together with manumycin. These results suggest that the basal levels of activated NF-kappaB in cortical neurons are maintained partially by synaptic activity involving N-methyl- D-aspartate (NMDA) and AMPA/kainate glutamate receptors, coupled to activation of an Src-family tyrosine kinase and a p21(Ras)-like guanosine triphosphatase (GTPase) in a cGMP-dependent manner. The results are intriguing in the light of the recent identification of a synaptic p21(Ras) activator stimulated by cGMP.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol.

Atypical antipsychotic drugs, such as clozapine, show many differences in their actions as compared to typical antipsychotic drugs, such as haloperidol. In particular, the neuroanatomical substrates responsible for the superior therapeutic profile of clozapine are unknown. In order to identify regions of the CNS which are affected either differentially or in parallel by clozapine and haloperidol, we have used 2-deoxyglucose autoradiography to monitor local cerebral glucose utilisation (LCGU), in parallel with in situ hybridisation to monitor the expression of five immediate-early genes (c-fos, fos B, fra 1, fra 2 and zif 268). Clozapine (20 mg/kg i.p.) caused a reduction in LCGU in many areas of the psychosis-related corticolimbothalamic and Papez circuits, such as the anterior cingulate and retrosplenial cortices and the mammillary body. Haloperidol (1 mg/kg i.p.) showed less ability to modulate LCGU in these regions. Clozapine also increased immediate-early gene expression in these limbic circuits, although the pattern of induction was different for each gene, and also differed from the pattern of effects on LCGU. The only region which displayed similar effects with both antipsychotics was the anteroventral thalamus, with LCGU and c-fos mRNA expression being altered similarly by both drugs. This further supports the hypothesis of the thalamus being a common site of antipsychotic action. Since the Papez circuit has been implicated in emotive learning, and to be involved in mediating the negative symptoms associated with schizophrenia, the greater action of clozapine on regions within this circuit may also provide clues to the atypical antipsychotic's superior efficacy against negative symptoms. This is one of the first studies which provides a direct comparison of regional activity as assessed by LCGU and by a panel of IEGs. The results emphasise the necessity of monitoring a number of different parameters of regional activity in order to identity the neuroanatomical substrate for actions of a drug in the CNS.

Animals↗
PubMed2001

ZNF265--a novel spliceosomal protein able to induce alternative splicing.

The formation of the active spliceosome, its recruitment to active areas of transcription, and its role in pre-mRNA splicing depends on the association of a number of multifunctional serine/arginine-rich (SR) proteins. ZNF265 is an arginine/serine-rich (RS) domain containing zinc finger protein with conserved pre-mRNA splicing protein motifs. Here we show that ZNF265 immunoprecipitates from splicing extracts in association with mRNA, and that it is able to alter splicing patterns of Tra2-beta1 transcripts in a dose-dependent manner in HEK 293 cells. Yeast two-hybrid analysis and immunoprecipitation indicated interaction of ZNF265 with the essential splicing factor proteins U1-70K and U2AF(35). Confocal microscopy demonstrated colocalization of ZNF265 with the motor neuron gene product SMN, the snRNP protein U1-70K, the SR protein SC35, and with the transcriptosomal components p300 and YY1. Transfection of HT-1080 cells with ZNF265-EGFP fusion constructs showed that nuclear localization of ZNF265 required the RS domain. Alignment with other RS domain-containing proteins revealed a high degree of SR dipeptide conservation. These data show that ZNF265 functions as a novel component of the mRNA processing machinery.

Active Transport, Cell Nucleus↗
PubMed2001

Activation of p44/p42 MAP kinase in striatal neurons via kainate receptors and PI3 kinase.

The members of the mitogen-activated protein (MAP) kinase family -- p44/p42 MAP kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAP kinase (p38) are known to be important mediators of the physiological plasticity or neurotoxicity induced in the striatum by activation of ionotropic glutamate receptors. However, our knowledge of the class of glutamate receptor and the intracellular pathways involved derives totally from studies on embryonic neurons, where the mechanisms are likely to be totally different from those operating in mature neurons. In superfused striatal slices from adult rats, NMDA and kainate, but not AMPA, were found to activate ERK. No activation of p38 or JNK was detected following treatment with any ionotropic glutamate receptor agonist. The activation of ERK by kainate was blocked by the ERK kinase (MEK) inhibitor PD98059, and the PI3 kinase inhibitor wortmannin, but not by the p38 MAP kinase inhibitor SB203580. This provides evidence for a novel pathway linking striatal kainate receptors to ERK activation via PI3 kinase and MEK.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Tumor necrosis factor receptor 2 gene (TNFRSF1B) in genetic basis of coronary artery disease.

Tumor necrosis factor (TNF)-alpha has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNF-RSF1B) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSF1B is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSF1B in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSF1B marker with CAD (chi2=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs. absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1-9.4, P<0.0001; in CA16 heterozygotes OR was 1.3, 95% CI 0.94-1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs. 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20-0.52, P<0.0001; in heterozygotes OR 0.41, 95% CI 0.26-0.63, P<0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0-1.9, P=0.027). Apolipoprotein A-I was elevated (P<0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1 +/- 0.1 ng/ml in CAD vs. 3.2 +/- 0.1 in control (P<0.0001), 5.2 +/- 0.1 in the presence vs. 4.6 +/- 0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2 +/- 0.2 (no angina), 5.0 +/- 0.1 (stable angina), 5.4 +/- 0.2 (unstable angina; P=0.003). sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor beta and homocysteine and was influenced by TNFRSF1B genotype. Thus genetic variation in or near the TNFRSF1B locus may predispose to CAD.

Adult↗