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  • NMDA receptor trafficking at recurrent synapses stabilizes the state of the CA3 network.

    23 July 2018

    Metaplasticity describes the stabilization of synaptic strength such that strong synapses are likely to remain strong while weak synapses are likely to remain weak. A potential mechanism for metaplasticity is a correlated change in both N-methyl-D-aspartate (NMDA) receptor-mediated postsynaptic conductance and synaptic strength. Synchronous activation of CA3-CA3 synapses during spontaneous bursts of population activity caused long-term potentiation (LTP) of recurrent CA3-CA3 glutamatergic synapses under control conditions and depotentiation when NMDA receptors were partially blocked by competitive antagonists. LTP was associated with a significant increase in membrane-bound NMDA receptors, whereas depotentiation was associated with a significant decrease in membrane-bound NMDA receptors. During burst activity, further depotentiation could be induced by sequential reductions in antagonist concentration, consistent with a depotentiation-associated reduction in membrane-bound NMDA receptors. The decrease in number of membrane-bound NMDA receptors associated with depotentiation reduced the probability of subsequent potentiation of weakened synapses in the face of ongoing synchronous network activity. This molecular mechanism stabilizes synaptic strength, which in turn stabilizes the state of the CA3 neuronal network, reflected in the frequency of spontaneous population bursts.

  • Altered NGF response but not release in the aged septo-hippocampal cholinergic system.

    23 July 2018

    An important aspect of aging and Alzheimer's disease (AD) pathology includes the degeneration of basal forebrain cholinergic neurons (BFCNs), possibly due to disrupted nerve growth factor (NGF) signaling. Previous studies on disrupted NGF signaling have focused on changes in retrograde transport. This study focuses on two other possible mechanisms for loss of trophic support: diminished release of NGF from hippocampal neurons or diminished TrkA receptor response of BFCNs to NGF. We measured NGF levels in the effluent of hippocampal slices from young and aged rats in response to potassium chloride and glutamate. We found that release of NGF was not altered in aged hippocampal slices compared to slices from young controls. To measure the in situ response of the BFCNs to NGF, we injected NGF intraparenchymally into the right hippocampus of young and aged rats. Injections of cytochrome C served as controls. Fifteen minutes post-administration, a dramatic increase in TrkA immunoreactivity was found in the cell bodies of medial septal neurons. We found that this rapid response was blunted in aged rats compared to young adult controls. To determine whether retrograde transport was necessary for this rapid response, we injected colchicine prior to NGF injection. The NGF-induced upregulation was not blocked by colchicine, suggesting that this acute response was not dependent on classical retrograde transport. Since cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, the loss of acute responsivity to NGF in the BFCNs may also play a role in these processes.

  • Inhibition of cyclic AMP accumulation in intact NCB-20 cells as a direct result of elevation of cytosolic Ca2+.

    23 July 2018

    Earlier studies established that adenylyl cyclase in NCB-20 cell plasma membranes is inhibited by concentrations of Ca2+ that are achieved in intact cells. The present studies were undertaken to prove that agents such as bradykinin and ATP, which elevate the cytosolic Ca2+ concentration ([Ca2+]i) from internal stores in NCB-20 cells, could inhibit cyclic AMP (cAMP) accumulation as a result of their mobilization of [Ca2+]i and not by other mechanisms. Both bradykinin and ATP transiently inhibited [3H]cAMP accumulation in parallel with their transient mobilization of [Ca2+]i. The [Ca2+]i rise stimulated by bradykinin could be blocked by treatment with thapsigargin; this thapsigargin treatment precluded the inhibition of cAMP accumulation mediated by bradykinin (and ATP). A rapid rise in [Ca2+]i, as elicited by bradykinin, rather than the slow rise evoked by thapsigargin was required for inhibition of [3H]cAMP accumulation. Desensitization of protein kinase C did not modify the inhibitory action of bradykinin on [3H]cAMP. Effects of Ca2+ on phosphodiesterase were also excluded in the present studies. The accumulated data are consistent with the hypothesis that hormonal mobilization of [Ca2+]i leads directly to the inhibition of cAMP accumulation in these cells and presumably in other cells that express the Ca(2+)-inhibitable form of adenylyl cyclase.

  • Protein III, a neuron-specific phosphoprotein: variant forms found in human brain.

    23 July 2018

    Protein III is a neuron-specific phosphoprotein which consists of two polypeptides, IIIa (Mr 74 kD) and IIIb (Mr 55 kD). This phosphoprotein has previously been shown to be associated with synaptic vesicles. In the present investigation, we have examined Protein III in human brain tissue. In contrast to observations in rat brain, where only one form of Protein IIIb (Mr 55 kD) has been found, in human brain tissue three variants of Protein IIIb, designated Protein IIIb1 (Mr 55 kD), Protein IIIb2 (Mr 57 kD) and Protein IIIb3 (Mr 59 kD), were observed by both biochemical and immunochemical assays. Protein IIIa from human brain also exhibited three variants in electrophoretic mobility. Peptide maps of Proteins IIIa and IIIb revealed that the differences in electrophoretic mobility of the variants of these proteins were preserved in variants (Mr 18kD, Mr20kD, and Mr22kD) of a smaller peptide fragment. These variant forms of Protein III were studied in brains from individuals without any history of neurological or psychiatric illness, as well as from individuals who had suffered from one of several types of neuropathological conditions, such as chronic alcoholism, Alzheimer's disease, multi-infarct dementia, and Parkinson's disease. Some differences were observed in the distribution of variants among the various clinical categories.

  • Ionotropic glutamate receptor subunit expression in the rat hippocampus: lack of an effect of a long-term ethanol exposure paradigm.

    23 July 2018

    BACKGROUND: Studies have shown that acute ethanol exposure inhibits ionotropic glutamate receptor function and that long-term ethanol exposure results in maladaptive increases in the expression of some of these receptors in neurons. It has been postulated that these changes, when unopposed by ethanol, contribute, in part, to the hyperexcitability associated with ethanol withdrawal. In this study, we compared the effect of long-term ethanol exposure on the hippocampal expression levels of subunits belonging to the three families of ionotropic glutamate receptors. METHODS: Adult male Sprague-Dawley rats were fed an ethanol-containing diet for 16 days. This diet contained 0% ethanol on days 1 and 2, 3% on days 3 and 4, 5% on days 5 to 7, and 6.7% on days 8 to 16. Control rats received an equivalent amount of an isocaloric diet without ethanol. Rats were killed on day 16 at the peak of ethanol consumption. Hippocampal homogenates were prepared by sonication and analyzed by Western immunoblotting techniques. On a separate group of rats, we measured withdrawal scores and audiogenic seizures on day 17. RESULTS: Ethanol-exposed rats had significantly higher withdrawal scores, and a significantly higher percentage of them developed audiogenic seizures; this indicates that the 16-day ethanol diet induces ethanol dependence. Unexpectedly, we found that expression of NR1 (including the expression of NR1 subunits containing the N1, C1, and C2 inserts), NR2A, NR2B, NR2C, GluR1, GluR2/3, GluR5, GluR6/7, and KA2 subunits was not altered in hippocampal homogenates from ethanol-exposed rats. CONCLUSIONS: These results indicate that maladaptive changes in the hippocampal expression levels of ionotropic glutamate receptor subunits do not always occur in ethanol-dependent rats. Consequently, other mechanisms must mediate the hyperexcitability state associated with ethanol withdrawal in these animals.

  • Development of synapsin I and synapsin II in intraocular hippocampal transplants.

    23 July 2018

    Previous studies have indicated that the appearance of synaptic vesicle-associated proteins known as the synapsins is one indicator of synapse formation. In this study, the levels and morphological distribution of synapsin I and synapsin IIa and IIb were studied in intraocular hippocampal transplants and in situ in the intact hippocampus. No detectable levels of either synapsin I or synapsin II were found in the fetal brain. The in situ levels of the synapsins exhibited parallel increases rapidly after birth, reaching peak levels at 8 weeks, after which a slight decline was noted in synapsin I and synapsin IIb. In hippocampal transplants, a comparable increase in the synapsins was seen during the first 8 weeks in oculo. It is likely that the synapse formation in the hippocampal transplants represents synapses from neurons within the transplant, as well as from various peripheral ganglia that send collaterals into the graft. Peripheral and central synapses express different synapsin I: synapsin IIa and IIb ratios. When the ratios of the synapsin proteins in hippocampal transplants were examined ratios essentially identical to those seen in the normal hippocampus were found, despite the numerous peripheral neurites innervating the grafts. Immunohistochemical studies supported the immunoblot data, showing no detectable immunofluorescence with synapsin antibodies in fetal or newborn hippocampal formation. The density of immunoreactive profiles increased substantially both in transplants and in the hippocampal formation in situ during the first 2 postnatal months. In conclusion, the present data demonstrate that hippocampal transplants in oculo can develop significant levels of the synapsins and that there is no time lag in development in these levels compared to the hippocampal formation in situ.

  • An analysis of postmortem brain samples from 32 alcoholic and nonalcoholic individuals for protein III, a neuronal phosphoprotein.

    23 July 2018

    Protein phosphorylation is a primary mechanism of intracellular signal transduction, and abnormalities in protein phosphorylation have been implicated in the pathogenesis of several specific diseases. Protein III is a neuronal phosphoprotein that is associated with synaptic vesicles and is probably involved in the regulation of neurotransmitter release. Analysis of 32 postmortem brains has confirmed our previous report that variant forms of protein III with higher apparent molecular weights are found frequently in the brains of alcoholic individuals but rarely in the brains of nonalcoholic individuals who did not suffer from any other medical or neuropsychiatric disorders. Eight of 14 (57%) brain samples from alcoholic individuals and four of eight (50%) brain samples from suspected alcoholic individuals had variant forms, while none of 10 samples from nonalcoholic individuals had variant forms. Previous data indicate that variant forms of protein III are also associated with other neurodegenerative conditions, including various dementias, and, possibly, normal aging.

  • Synapsin Ia, synapsin Ib, protein IIIa, and protein IIIb, four related synaptic vesicle-associated phosphoproteins, share regional and cellular localization in rat brain.

    23 July 2018

    The regional and cellular distribution of four synaptic vesicle-associated proteins, synapsins Ia and Ib (Mr 86,000 and 80,000, collectively referred to as synapsin I) and proteins IIIa and IIIb (Mr 74,000 and 55,000, collectively referred to as protein III), has been compared in selected rat brain regions, using both radioimmunoassays and back-phosphorylation assays. Lesions of several neuronal populations in the basal ganglia (corticostriatal fibers, intrinsic striatal neurons, striatonigral fibers, nigrostriatal fibers) induced decreases in the levels of these various proteins that were highly correlated (r = 0.96-0.97). Moreover, the synaptic vesicle-associated phosphoproteins displayed a similar and widespread distribution throughout the CNS. This evidence for colocalization indicates that the majority of, and possibly all, CNS neurons and nerve terminals may contain both forms of synapsin I and both forms of protein III.

  • Functional adaptation of the N-methyl-D-aspartate receptor to inhibition by ethanol is modulated by striatal-enriched protein tyrosine phosphatase and p38 mitogen-activated protein kinase.

    23 July 2018

    The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na⁺ and Ca²⁺ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. We have found that short-term ethanol application inhibits the NMDAR activity via striatal enriched protein tyrosine phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of ethanol inhibition of NMDAR currents. In addition, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (MAPK), and these proteins are members of the NMDAR super molecular complex. Here we demonstrate, using whole-cell electrophysiological recording, Western blot analysis, and pharmacological manipulations, that neurons exposed to a 3-h, 45 mM ethanol treatment develop an adaptive attenuation of short-term ethanol inhibition of NMDAR currents in brain slices. Our results suggest that this adaptation of NMDAR responses is associated with a partial inactivation of STEP61, an activation of p38 MAPK, and a requirement for NR2B activity. Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons.

  • Acute effects of ethanol on recombinant kainate receptors: lack of role of protein phosphorylation.

    23 July 2018

    This study examined the acute actions of ethanol on recombinant rat GluR6 kainate receptors expressed in Xenopus oocytes and HEK 293 cells. Electrophysiological recordings showed that co-application of ethanol with submaximal kainate concentrations resulted in similar inhibition of kainate-gated currents in both expression systems. Manipulation of intracellular phosphorylation pathways by intracellular dialysis with a solution without ATP and GTP did not modify the inhibitory effects of ethanol. Moreover, co-transfection of GluR6 receptor subunits with PKA-alpha catalytic subunit or the calcium/calmodulin-dependent protein kinase II (CamKII) catalytic fragment did not change the sensitivity of the receptor to ethanol. Treatment of Xenopus oocytes with specific inhibitors of PKC, PKA, CamKII, tyrosine kinases, and serine-threonine protein phosphatases did not affect the 100 mM ethanol-induced inhibition of GluR6 receptor-mediated currents. Biochemical experiments with transiently transfected HEK 293 cells confirmed published reports that GluR6 receptors are minimally phosphorylated under basal conditions in these cells and also revealed that acute ethanol did not increase GluR6 phosphorylation. These results suggest that, under our experimental conditions, ethanol inhibits recombinant GluR6 receptor function by a direct effect on the receptor rather than an indirect action via protein phosphorylation.

  • Clinical Lectureship Positions now open for application (Closing date: 3 June 2015)

    5 May 2015

    Applications are invited for six posts under the NIHR Integrated Academic Training Pathway. These are fixed-term, four-year posts which offer excellent opportunities to undertake high quality research within a clinically excellent environment and to undertake clinical work towards gaining a CCT.

  • From lab bench to green bench

    9 December 2015

    Dr Jessica Ash, from the Department of Psychiatry visited MP George Freeman, the life sciences minister, at the House of Commons for a week in Westminster.

  • Human trials suggest ‘rescued’ drug could be safer treatment for bipolar disorder

    9 December 2015

    A drug destined for the scrap heap has been rescued by Oxford scientists, who may have found it a new role in treating bipolar disorder.

  • Reported self-inflicted harm cases have steadily risen in UK since 2008

    9 May 2016

    The number of cases of self-harm presenting to hospitals in England has risen steadily since 2008, especially among men, reveals research co-ordinated by the Centre for Suicide Research at Oxford University Department of Psychiatry, published in the online journal BMJ Open.

  • Professor Michael Sharpe is named as Psychiatrist of the Year

    7 November 2014

    Professor Sharpe has been named as Psychiatrist of the Year at the Royal College of Psychiatrists Awards Ceremony in London

  • Self-help from the stands

    18 October 2013

    Gill Oliver probes mind and motivations of the Watford FC-supporting Oxford University Professor of Clinical Psychology

  • Simple blood test gives early warning of Alzheimer's

    8 July 2014

    BBC News online, 08/07/14, James Gallagher: Scientists have made a ‘major step forward’ in developing a blood test to predict the onset of Alzheimer's disease. Research in more than 1,000 people has identified a set of proteins in the blood which can predict the start of the dementia with 87% accuracy. The findings, published in the journal Alzheimer's & Dementia, will be used to improve trials for new dementia drugs.

  • Largest epidemiological study of epilepsy and psychiatric disorders

    22 July 2013

    In a recent Lancet paper, Seena Fazel together with Achim Wolf and Charles Newton from this department, reports that "people with epilepsy are 11 times more likely to die prematurely than the general population, and the risk appears to be substantially higher for individuals with common co-existing psychiatric illnesses." He adds: "standard psychiatric checks could help reduce the risk of premature deaths in people with epilepsy."

  • Congratulations Kate!

    22 July 2013

    Dr Kate Saunders has been awarded the Johnstone & Florence Stoney studentship by the British Federation of Women Graduates after competitive interview. The Studentship will be officially awarded on Thursday, October 17th before the Sybil Campbell Collection Annual Lecture at the University Women’s Club, in 2 Audley Square, Mayfair.

  • Psychological Benefits for Prisoners doing Yoga

    11 July 2013

    Yoga could help address mental health problems in prisons Yoga can improve mood and mental wellbeing among prisoners, an Oxford University study suggests, and may also have an effect on impulsive behaviour.