%0 Journal Article
%~ PubMed
%A Svahn, Adam J
%A Graeber, Manuel B
%A Ellett, Felix
%A Lieschke, Graham J
%A Rinkwitz, Silke
%A Bennett, Maxwell R
%A Becker, Thomas S
%T Development of ramified microglia from early macrophages in the zebrafish optic tectum.
%B Developmental Neurobiology
%D 2013
%C United States
%I John Wiley & Sons, Inc.
%V 73
%N 1
%P 60-71
%@ 1932-846X
%X Microglia, the resident macrophage precursors of the brain, are necessary for the maintenance of tissue homeostasis and activated by a wide range of pathological stimuli. They have a key role in immune and inflammatory responses. Early microglia stem from primitive macrophages, however the transition from early motile forms to the ramified mature resident microglia has not been assayed in real time. In order to provide such an assay, we used zebrafish transgenic lines in which fluorescent reporter expression is driven by the promoter of macrophage expressed gene 1 (mpeg1; Ellet et al., Blood. 117(4):e49-56, 2011). This enabled the investigation of the development of these cells in live, intact larvae. We show that microglia develop from highly motile amoeboid cells that are engaged in phagocytosis of apoptotic cell bodies into a microglial cell type that rapidly morphs back and forth between amoeboid and ramified morphologies. These morphing microglia eventually settle into a typical mature ramified morphology. Developing microglia frequently come into contact with blood capillaries in the brain, and also frequently contact each other. Up to 10 days post fertilization, microglia were observed to undergo symmetric division. In the adult optic tectum, the microglia are highly branched, resembling mammalian microglia. In addition, the mpeg1 transgene also labelled highly branched cells in the skin overlying the optic tectum from 8-9 days post-fertilization, which likely represent Langerhans cells. Thus, the development of zebrafish microglia and their cellular interactions was studied in the intact developing brain in real time and at cellular resolution. ?? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
%Z FOR Codes: 1109


%0 Journal Article
%~ PubMed
%A Lagopoulos, J
%A Hermens, D F
%A Hatton, S N
%A Battisti, R A
%A Tobias-Webb, J
%A White, D
%A Naismith, S L
%A Scott, E M
%A Ryder, W J
%A Bennett, M R
%A Hickie, I B
%T Microstructural white matter changes are correlated with the stage of psychiatric illness.
%B Translational Psychiatry
%D 2013
%C United Kingdom
%I Nature Publishing Group
%V 3
%N 
%P e248
%@ 2158-3188
%X 
%Z FOR Codes: 110319


%0 Journal Article
%~ PubMed
%A Kassem, Mustafa S
%A Lagopoulos, Jim
%A Stait-Gardner, Tim
%A Price, William S
%A Chohan, Tariq W
%A Arnold, Jonathon C
%A Hatton, Sean N
%A Bennett, Maxwell R
%T Stress-Induced Grey Matter Loss Determined by MRI Is Primarily Due to Loss of Dendrites and Their Synapses.
%B Molecular Neurobiology
%D 2013
%C United States
%I Humana Press, Inc.
%V 47
%N 2
%P 645-661
%@ 1559-1182
%X 
%Z FOR Codes: 1109


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%T The discovery of a new class of synaptic transmitters in smooth muscle fifty years ago and amelioration of coronary artery thrombosis.
%B Acta Physiologica
%D 2013
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 207
%N 2
%P 236-243
%@ 1748-1716
%X 
%Z FOR Codes: 60601


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%A Farnell, Les
%A Gibson, William G
%T A Model of Neuregulin Control of NMDA Receptors on Synaptic Spines.
%B Bulletin of Mathematical Biology
%D 2012
%C United States
%I Springer New York LLC
%V 74
%N 3
%P 717-735
%@ 1522-9602
%X Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of Src family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by Src kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia.
%Z FOR Codes: 60601


%0 Journal Article
%~ PubMed
%A Hatton, Sean N
%A Lagopoulos, Jim
%A Hermens, Daniel F
%A Naismith, Sharon L
%A Bennett, Maxwell R
%A Hickie, Ian B
%T Correlating anterior insula gray matter volume changes in young people with clinical and neurocognitive outcomes: an MRI study.
%B BMC Psychiatry
%D 2012
%C United Kingdom
%I BioMed Central Ltd.
%V 12
%N 1
%P 45
%@ 1471-244X
%X ABSTRACT: BACKGROUND: The anterior insula cortex is considered to be both the structural and functional link between experience, affect, and behaviour. Magnetic resonance imaging (MRI) studies have shown changes in anterior insula gray matter volume (GMV) in psychosis, bipolar, depression and anxiety disorders in older patients, but few studies have investigated insula GMV changes in young people. This study examined the relationship between anterior insula GMV, clinical symptom severity and neuropsychological performance in a heterogeneous cohort of young people presenting for mental health care. RESULTS: Compared to healthy participants, patients had significantly reduced GMV in the left anterior insula (t=2.05, p=.042) which correlated with reduced performance on a neuropsychological task of attentional set-shifting (rho=0.32, p=.016). Changes in right anterior insula GMV was correlated with increased symptom severity (r=.29, p=.006) and more positive symptoms (r=.32, p=.002). CONCLUSIONS: By using the novel approach of examining a heterogeneous cohort of young depression, anxiety, bipolar and psychosis patients together, this study has demonstrated that insula GMV changes are associated with neurocognitive deficits and clinical symptoms in such young patients.
%Z FOR Codes: 110319 110902 170101


%0 Journal Article
%~ PubMed
%A Werry, E L
%A Liu, G J
%A Lovelace, M D
%A Nagarajah, R
%A Bennett, M R
%T Glutamate potentiates lipopolysaccharide-stimulated interleukin-10 release from neonatal rat spinal cord astrocytes.
%B Neuroscience
%D 2012
%C United Kingdom, France
%I Pergamon
%V 207
%N 
%P 12-24
%@ 0306-4522
%X Interleukin-10 (IL-10) has important anti-inflammatory effects and can be protective in inflammatory conditions, such as chronic pain and infection. Exploring factors that modulate IL-10 levels may provide insight into pathomechanisms of inflammatory conditions and may provide a method of neuroprotection during these conditions. Lipopolysaccharide (LPS) stimulation of astrocytes is a source of IL-10; hence, it is of interest to investigate factors that modulate this process. Glutamate is present in increased concentrations in inflammatory conditions, and astrocytes also express glutamate receptors. The present study, therefore, investigated whether glutamate modulates LPS stimulation of IL-10 release from neonatal spinal cord astrocytes. Enzyme-linked immunosorbent assays (ELISAs) were used to quantify IL-10 release from cultured neonatal spinal cord astrocytes, and reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure IL-10 mRNA expression. Glutamate (1 mM) significantly increased LPS (1 ?g/ml)-stimulated IL-10 release from astrocytes by 166% and significantly upregulated IL-10 mRNA levels. Glutamate synergistically signaled through metabotropic glutamate receptor subgroups and the phospholipase C signaling pathway. Spinal cord astrocytes may, therefore, play a larger anti-inflammatory role than first thought in situations where glutamate and a high concentration of Toll-like receptor 4 (TLR4) agonists are present.
%Z FOR Codes: 60602


%0 Journal Article
%A Bennett, Maxwell
%A Hacker, Peter MS
%T Criminal Law as It Pertains to Patients Suffering from Psychiatric Diseases
%B Bioethical Inquiry
%D 2011
%C Netherlands
%I Springer Netherlands
%V 8
%N 1
%P 45-58
%@ 1176-7529
%X 
%Z FOR Codes: 220106 220105 111714


%0 Journal Article
%~ PubMed
%A Werry, Eryn L
%A Liu, Guo Jun
%A Lovelace, Michael D
%A Nagarajah, Rajini
%A Hickie, Ian B
%A Bennett, Max R
%T Lipopolysaccharide-Stimulated Interleukin-10 Release From Neonatal Spinal Cord Microglia is Potentiated by Glutamate.
%B Neuroscience
%D 2011
%C United Kingdom, France
%I Pergamon
%V 175
%N 
%P 93-103
%@ 0306-4522
%X Interleukin-10 (IL-10) is a cytokine with important endogenous and therapeutic anti-inflammatory effects. Given this, it is of interest to investigate factors that modulate IL-10 levels in the central nervous system. IL-10 is released after lipopolysaccharide (LPS) stimulation of microglia. Microglia also express functional glutamate receptors and in inflammatory conditions are exposed to increased levels of glutamate. The aim of this research, then, is to investigate whether glutamate can modulate lipopolysaccharide stimulation of IL-10 release from neonatal rat spinal cord microglia. Enzyme-linked immunosorbent assays (ELISAs) were used to quantify IL-10 release from cultured neonatal spinal cord microglia and reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure IL-10 mRNA expression. Glutamate (1 mM) significantly increased LPS (1 ??g/ml)-stimulated IL-10 release from microglia by 172% (EC(50) of 103 ??M) and significantly upregulated IL-10 mRNA levels. Glutamate potentiated LPS-stimulated IL-10 release by binding all subtypes of glutamate receptor. These results show that glutamate substantially increases the release of an anti-inflammatory cytokine from neonatal spinal cord microglia activated by a high concentration of LPS.
%Z FOR Codes: 1109


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell R
%A Hacker, Peter M S
%T Reply to critical review by professor John Smythies.
%B Perception
%D 2011
%C United Kingdom
%I Pion Ltd.
%V 40
%N 2
%P 249-251
%@ 0301-0066
%X 
%Z FOR Codes: 110906


%0 Journal Article
%~ PubMed
%A Boucher, A A
%A Arnold, J C
%A Hunt, G E
%A Spiro, A
%A Spencer, J
%A Brown, C
%A McGregor, I S
%A Bennett, M R
%A Kassiou, M
%T Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test.
%B Neuroscience
%D 2011
%C United Kingdom, France
%I Pergamon
%V 189
%N 2011
%P 170-7
%@ 0306-4522
%X There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress.
%Z FOR Codes: 111599 110999


%0 Journal Article
%~ PubMed
%A Bennett, M R
%T Schizophrenia: Susceptibility genes, dendritic-spine pathology and gray matter loss.
%B Progress in neurobiology
%D 2011
%C United Kingdom
%I Pergamon
%V 95
%N 3
%P 275-300
%@ 1873-5118
%X Gray matter loss in the cortex is extensive in schizophrenia, especially in the prefrontal-temporal-network (PTN). Several molecules such as neuregulin-1 (NRG1) and its ErbB4 receptor are encoded by candidate susceptibility genes for schizophrenia. The question arises as to how these genes might contribute to the observed changes in gray matter. It is suggested that one pathway involves molecules such as NRG1/ErbB4 determining the efficacy of N-methyl-D-aspartate receptors (NMDARs) found on dendritic spines at synapses in the PTN. The growth of dendritic spines is modulated by NRG1/ErbB4 through NMDARs as these activate small Rho-GTPases, such as kalirin, which control the actin cytoskeleton in the spines responsible for their growth. Another pathway involves NRG1/ErbB determining the proliferation and differentiation of oligodendrocytes in the white matter as well as their capacity for myelination, the integrity of which determines the stability of nerve terminals on dendritic spines. A causal chain is established between failure of the products of susceptibility genes for schizophrenia, the decrease of dendritic spines and synaptic terminals, and the loss of gray matter. It is suggested than an important focus for future research in schizophrenia is to identify interventions that prevent the loss of dendritic spines and synapses during the prodromal period or earlier during development as well as to re-establish dendritic spines and synapses lost subsequent to this period. This will help reestablish neural networks in the PTN and so the loss of gray matter in the PTN.
%Z FOR Codes: 60603


%0 Book Section
%A Bennett, Maxwell
%T Seele und Geist-zur Geschichte zweier Begriffe'
%B Images of the Mind: Bildwelten des Geistes aus Kunst und Wissenschaft
%D 2011
%C Germany
%I Wallstein Verlag
%V 
%N 
%P 13-24
%@ 9783835309739
%E Schmitz, Colleen M.
%E Kesner, Ladislav
%X 
%Z FOR Codes: 110906


%0 Journal Article
%~ PubMed
%A Bennett, M R
%T The prefrontal-limbic network in depression: A core pathology of synapse regression.
%B Progress in Neurobiology
%D 2011
%C United Kingdom
%I Pergamon
%V 93
%N 4
%P 457-467
%@ 1873-5118
%X Grey matter loss occurs in different components of the prefrontal-limbic network (PLN) implicated in major depressive disorder (MDD). This must be accounted for by specific pathologies of cells and their processes that comprise the grey matter. In order to identify these a quantitative evaluation of the contributions of neurons, glial cells, blood vessels and extracellular space to the grey matter volume is determined. This forms the basis of evaluating the various claims that the core pathology of certain cell types and/or their processes are responsible for the grey matter loss. It is concluded that it is the loss of synapses and concomitantly that of the dendrites on which they normally impinge that accounts quantitatively for the major loss of grey matter in different components of the PLN in depression.
%Z FOR Codes: 606


%0 Journal Article
%~ PubMed
%A Bennett, M R
%T The prefrontal-limbic network in depression: Modulation by hypothalamus, basal ganglia and midbrain.
%B Progress in Neurobiology
%D 2011
%C United Kingdom
%I Pergamon
%V 93
%N 4
%P 468-487
%@ 1873-5118
%X The anterior cingulate cortex, amygdala and hippocampus form part of an interconnected prefrontal neocortical and limbic archicortical network that is dysregulated in major depressive disorders (MDD). Modulation of this prefrontal-limbic network (PLN) is principally through the hypothalamus, basal ganglia and midbrain. Here the likely mechanisms by which these modulations are affected are described and the implications of their failure for depression associated with suicidal diathesis, late-life and psychoses discussed.
%Z FOR Codes: 606


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%A Farnell, Les
%A Gibson, William G
%T A Model of NMDA Receptor Control of F-actin Treadmilling in Synaptic Spines and Their Growth.
%B Bulletin of mathematical biology
%D 2010
%C United States
%I Springer New York LLC
%V 73
%N 0
%P 2109-31
%@ 1522-9602
%X Synaptic spines grow as a consequence of the formation of F-actin filaments at the spine head. The dynamics of F-actin in the spine head upon excitation of N-methy-D-aspartate (NMDA) receptors has recently been investigated experimentally, but there is no quantitative account of how these dynamic changes occur upon activation of these receptors; this we now supply. Dynamics of F-actin at the apex of lamellipodia have been investigated in detail, giving rise to the treadmilling theory of F-actin dynamics, involving catalysis by profilin, for which quantitative models are now available. Here, we adapt such a model to describe the dynamics of F-actin in the synaptic-spine head and show that it gives quantitative descriptions of this treadmilling phenomena which are well fitted by Monte Carlo simulations. Next, the means by which excitation of NMDA receptors enhances the activity of profilin through activity of the Rho small GTPase RhoA and the specific kinase ROCK is discussed. This is then used to model the NMDA receptor excitatory enhancement of profilin and so the treadmilling process of F-actin dynamics in spine growth. Such modelling provides a quantitative description of the synaptic-spine dynamics of the filamentous to globular actin ratio that is observed experimentally.
%Z FOR Codes: 606


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell R
%T Synapse regression in depression: the role of 5-HT receptors in modulating NMDA receptor function and synaptic plasticity.
%B The Australian and New Zealand Journal of Psychiatry
%D 2010
%C United Kingdom, Aust
%I Informa Healthcare
%V 44
%N 4
%P 301-308
%@ 1440-1614
%X Depression is accompanied by an increase in activity in the amygdala and a decrease in the rostral anterior cingulate cortex (rACC), with the former attributed to a failure of the latter to exert its normal inhibitory influence. This failure is likely due to regression of synaptic connections between the rACC and the amygdala, a process reversed in part by selective serotonin reuptake inhibitors (SSRIs). The present work presents a hypothesis as to how SSRIs might bring about this process and hence normalization of activity, at least in patients that are responsive to SSRIs. Serotonin receptors of the excitatory 5-HT(2A)R class increase N-methyl-D-aspartate receptor (NMDAR) efficacy, while those of the inhibitory 5-HT(1A)R class decrease NMDAR efficacy. A decrease of 5-HT transporter (5-HTT) efficacy, either during human development through functional polymorphisms, or in animals through 5-HTT transgenic knockouts, is accompanied by a decrease in 5-HT(1A)R and hence an increase in excitability and NMDAR efficacy which drives an increase in synaptic spines in the amygdala. As the limbic region of the brain normally possesses high levels of 5-HT(1A)R the effect of loss of these is to increase excitation in this region, as is observed. Changes in the level of extracellular 5-HT in adult animals also modulates the density of synaptic spines, with these increasing with an increase in 5-HT, possibly as a consequence of increases in 5-HT(2A)R activity over that of 5-HT(1A)R. Increasing extracellular levels of 5-HT with SSRIs would then lead to an increase in excitability and in synaptic spines for afferents in the dorsal rostral anterior cingulate cortex but not in the ventral regions such as the amygdala that have few 5-HT(2A)R. This allows dorsal regions to once more exert their inhibitory influence over ventral regions. In this way, SSRIs may exert their effect in normalizing dorsal hypometabolism and ventral hypermetabolism in those suffering from depression.
%Z FOR Codes: 1109 606


%0 Journal Article
%~ Isi
%A Bennett, M.
%T Criminal law as it pertains to ''mentally incompetent defendants'': a McNaughton rule in the light of cognitive neuroscience
%B Australian and New Zealand Journal of Psychiatry
%D 2009
%C United Kingdom, Aust
%I Informa Healthcare
%V 43
%N 4
%P 289-299
%@ 0004-8674
%X 
%Z FOR Codes: 110319


%0 Journal Article
%~ PubMed
%A Shin, Jae-Won
%A Nguyen, Khoa
%A Pow, David
%A Knight, Toby
%A Buljan, Vlado
%A Bennett, Maxwell
%A Balcar, Vladimir
%T Distribution of Glutamate Transporter GLAST in Membranes of Cultured Astrocytes in the Presence of Glutamate Transport Substrates and ATP.
%B Neurochemical research
%D 2009
%C United States
%I Springer New York LLC
%V 34
%N 10
%P 1758-66
%@ 1573-6903
%X Neurotransmitter L-glutamate released at central synapses is taken up and "recycled" by astrocytes using glutamate transporter molecules such as GLAST and GLT. Glutamate transport is essential for prevention of glutamate neurotoxicity, it is a key regulator of neurotransmitter metabolism and may contribute to mechanisms through which neurons and glia communicate with each other. Using immunocytochemistry and image analysis we have found that extracellular D-aspartate (a typical substrate for glutamate transport) can cause redistribution of GLAST from cytoplasm to the cell membrane. The process appears to involve phosphorylation/dephosphorylation and requires intact cytoskeleton. Glutamate transport ligands L-trans-pyrrolidine-2,4-dicarboxylate and DL-threo-3-benzyloxyaspartate but not anti,endo-3,4-methanopyrrolidine dicarboxylate have produced similar redistribution of GLAST. Several representative ligands for glutamate receptors whether of ionotropic or metabotropic type, were found to have no effect. In addition, extracellular ATP induced formation of GLAST clusters in the cell membranes by a process apparently mediated by P2 receptors. The present data suggest that GLAST can rapidly and specifically respond to changes in the cellular environment thus potentially helping to fine-tune the functions of astrocytes.
%Z FOR Codes: 60105


%0 Journal Article
%~ PubMed
%A Liu, Guo Jun
%A Nagarajah, Rajini
%A Banati, Richard B
%A Bennett, Max R
%T Glutamate induces directed chemotaxis of microglia.
%B European Journal of Neuroscience
%D 2009
%C United Kingdom, Germ
%I Wiley-Blackwell Publishing Ltd.
%V 29
%N 6
%P 1108-1118
%@ 1460-9568
%X Microglia in the brain possess dynamic processes that continually sample the surrounding parenchyma and respond to local insults by rapidly converging on the site of an injury. One of the chemotaxic agents responsible for this response is ATP. Here we show that the transmitter glutamate is another such chemotaxic agent. Microglia exposed to glutamate increase their cell membrane ruffling and migrate to a source of glutamate in cell culture and in spinal cord slices. This chemotaxis is meditated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and metabotropic glutamate receptors on the microglia. Chemotaxis is dependent on redistribution of actin filaments in the cells and on tubulin following receptor activation. Thus glutamate, which is released at synapses as well as from damaged cells, can mediate rapid chemotaxic responses from microglial cells.
%Z FOR Codes: 110999


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%A Farnell, Les
%A Gibson, William G
%T P2X(7) regenerative-loop potentiation of glutamate synaptic transmission by microglia and astrocytes.
%B Journal of theoretical biology
%D 2009
%C United Kingdom
%I Academic Press
%V 261
%N 1
%P 1-16
%@ 0022-5193
%X P2X7 purinergic receptors have been implicated in chronic neuropathic and neuroinflammatory pain as well as in depression. These receptors are predominantly found in the central nervous system on microglial cells and on glutamatergic nerve terminals. Here, we develop hypotheses concerning mechanisms by which transient high-frequency impulse firing in glutamatergic terminals, such as occurs in nociceptor terminals accompanying neuropathic/neuroinflammatory pain, can lead to long-lasting changes in neural network function that is mediated by surrounding glial cells. The hypothesis consists of two parts. In the first, glutamate released by low-frequency (2Hz) terminal action potentials is insufficient to generate postsynaptic action potentials, but these are generated by brief high-frequency input bursts. Glutamate released by these bursts is partly removed by transporters on the enveloping astrocyte processes and also excites AMPA receptors on these processes, which then release ATP. This ATP is partly metabolised to adenosine, which acts on presynaptic A1 receptors to inhibit glutamate release. The remaining ATP acts on the presynaptic P2X7 receptors to facilitate glutamate release by both the high-frequency burst of action potentials as well as by a continuous low-frequency (2Hz) action potential firing that occurs in the absence of a neuropathic/neuroinflammatory insult. The positive feedback of terminal glutamate release, triggering astrocyte ATP release and leading to further glutamate release through activation of P2X7 receptors, is then sufficient to allow the normal low-frequency (2Hz) action potentials to now elicit postsynaptic action potentials after the insult is removed. In the second part of this model, the high concentration of ATP derived from astrocytes at the terminal attracts microglia by chemotaxis. The P2X7 receptors on these microglia are then engaged, resulting in microglia secreting the cytokine TNFalpha. This acts on postsynaptic TNF-R1 receptors to increase the number of AMPA receptors there, thus enhancing the efficacy of synaptic transmission. The TNFalpha also acts on presynaptic TNF-R1 to increase the amount of glutamate released by each nerve terminal impulse. Experimental tests can be made of this hypothesis that P2X7 receptors on the presynaptic terminal and those on the microglia synergistically act to ensure feedback pathways that reset to a high level the efficacy of synaptic transmission, thus ensuring chronic neuropathic/neuroinflammatory pain even when the initial insult has subsided.
%Z FOR Codes: 60199


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell
%T Positive and negative symptoms in schizophrenia: the NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression.
%B Australian & New Zealand Journal of Psychiatry
%D 2009
%C United Kingdom, Aus
%I Informa Healthcare
%V 43
%N 8
%P 711-721
%@ 1440-1614
%X Carlsson has put forward the hypothesis that the positive and negative symptoms of schizophrenia are due to failure of mesolimbic and mesocortical projections consequent on hypofunction of the glutamate N-methyl-d-aspartate (NMDA) receptor. The hypothesis has been recently emphasized in this Journal that the loss of synaptic spines with NMDA receptors, which can be precipitated by stress, can explain the emergence of positive symptoms such as hallucinations and that this synapse regression involves molecules such as neuregulin and its receptor ErbB4 that have been implicated in schizophrenia. In this essay these two hypotheses are brought together in a single scheme in which emphasis is placed on the molecular pathways from neuregulin/ErbB4, to modulation of the NMDA receptors, subsequent changes in the synaptic spine''s cytoskeletal apparatus and so regression of the spines. It is suggested that identification of the molecular constituents of this pathway will allow synthesis of suitable substances for removing the hypofunction of NMDA receptors and so the phenotypic consequences that flow from this hypofunction.
%Z FOR Codes: 110319


%0 Journal Article
%~ PubMed
%A Gunosewoyo, Hendra
%A Coster, Mark J
%A Bennett, Maxwell R
%A Kassiou, Michael
%T Purinergic P2X(7) receptor antagonists: Chemistry and fundamentals of biological screening.
%B Bioorganic & medicinal chemistry
%D 2009
%C United Kingdom
%I Pergamon-Elsevier Science Ltd
%V 17
%N 14
%P 4861-5
%@ 0968-0896
%X The purinergic P2X(7) receptor is a unique member of the ATP-gated P2X family. This receptor has been implicated in numerous diseases and many structurally diverse ligands have been discovered via high throughput screening. This perspective will attempt to highlight some of the most recent key findings in both the biology and chemistry.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Nguyen, Khoa
%A Shin, Jae-Won
%A Rae, Caroline
%A Nanitsos, Ellas
%A Acosta, Gabriela
%A Pow, David
%A Buljan, Vlado
%A Bennett, Maxwell
%A Else, Paul
%A Balcar, Vladimir
%T Rottlerin Inhibits (Na(+), K (+))-ATPase Activity in Brain Tissue and Alters D: -Aspartate Dependent Redistribution of Glutamate Transporter GLAST in Cultured Astrocytes.
%B Neurochemical research
%D 2009
%C United States
%I Springer New York LLC
%V 34
%N 10
%P 1767-74
%@ 1573-6903
%X The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibitor of protein kinase C-delta (PKC-delta) to obtain evidence that the activity-dependent distribution of glutamate transporter GLAST is regulated by PKC-delta mediated phosphorylation. Using immunofluorescence labelling for GLAST and deconvolution microscopy we have observed that D-aspartate-induced redistribution of GLAST towards the plasma membranes of cultured astrocytes was abolished by rottlerin. In brain tissue in vitro, rottlerin reduced apparent activity of (Na+, K+)-dependent ATPase (Na+, K+-ATPase) and increased oxygen consumption in accordance with its known activity as an uncoupler of oxidative phosphorylation ("metabolic poison"). Rottlerin also inhibited Na+, K+-ATPase in cultured astrocytes. As the glutamate transport critically depends on energy metabolism and on the activity of Na+, K+-ATPase in particular, we suggest that the metabolic toxicity of rottlerin and/or the decreased activity of the Na+, K+-ATPase could explain both the glutamate transport inhibition and altered GLAST distribution caused by rottlerin even without any involvement of PKC-delta-catalysed phosphorylation in the process.
%Z FOR Codes: 60105


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell R
%T Synapse formation and regression in the cortex during adolescence and in schizophrenia.
%B The Medical Journal of Australia
%D 2009
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd
%V 190
%N 4 Suppl
%P S14-S16
%@ 1326-5377
%X During adolescence, about 30% of the synapses formed during childhood in the dorsolateral prefrontal cortex (DLPC) are lost; in patients with schizophrenia, the synapse loss is about 60%. Studies of synapse loss in the neuromuscular junction have provided insights into the molecular basis of synapse formation and regression, thereby providing a paradigm for investigations of synapse loss in the DLPC. Research into some of these molecules in the DLPC has shown that they are crucial to synapse formation and regression. Further research in this field could examine when synapse loss in the DLPC of patients with schizophrenia occurs, and further elucidate how these molecules are involved in the development of schizophrenia.
%Z FOR Codes: 170101


%0 Book Section
%A Gibson, William
%A Farnell, Leslie
%A Bennett, Maxwell
%T A quantitative model of ATP-mediated calcium wave propagation in astrocyte networks
%B Mathematical Modeling of Biological Systems: Epidemiology, Evolution and Ecology, Immunology, Neural Systems and the Brain, and Innovative Mathematical Methods: v. 2
%D 2008
%C Switzerland
%I Birkhauser
%V 
%N 
%P 193-204
%@ 9780817645557
%E Deutsch, A
%E Bravo de la Parra, R
%E de Boer, R.J.
%E Diekmann, O.
%E Jagers, P.
%E Kisdi, E.
%E Kretzschmar, M
%E Lansky, P
%E Metz, H
%X 
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%A Farnell, Les
%A Gibson, William G
%T A quantitative model of cortical spreading depression due to purinergic and gap-junction transmission in astrocyte networks.
%B Biophysical journal
%D 2008
%C 9650 Rockville Pike, Bethesda, Md, 20814-3998
%I Biophysical Society
%V 95
%N 12
%P 5648-60
%@ 1542-0086
%X Spreading depression (SD), a propagating wave of electrical silence in the cortex and archicortex, involves depolarization of neurons and astrocytes for approximately 1 min, due principally to a large increase in extracellular K+. SD is accompanied by large increases in extracellular ATP and is blocked by glutamate N-methyl-D-aspartate receptor antagonists. As a principal means of transmission between astrocytes is through their release of ATP, we have investigated if a model in which SD is driven by the effects of astrocyte waves of ATP interacting with waves of glutamate release from neurons and astrocytes can give a quantitative account of experimental observations on SD. We show that the characteristics of SD and the accompanying extracellular ionic changes can be accommodated by such a model-whether astrocyte transmission is principally through the release of ATP, as in archicortex (hippocampus) and spinal cord, or via gap junctions, as in the neocortex. Furthermore, these models give quantitative accounts of the effects on the characteristics of SD of agents toxic for astrocytes and of gap-junction blockers. Finally, an additional series of critical tests of the model is suggested.
%Z FOR Codes: 110999


%0 Journal Article
%A Bennett, Maxwell
%T Consciousness and hallucinations in schizophrenia: the role of synapse regression
%B Australian and New Zealand Journal of Psychiatry
%D 2008
%C Australia
%I Informa Healthcare
%V 42
%N 
%P 915-931
%@ 0004-8674
%X 
%Z FOR Codes: 110319


%0 Journal Article
%~ PubMed
%A Gunosewoyo, Hendra
%A Guo, Jun Liu
%A Bennett, Maxwell R
%A Coster, Mark J
%A Kassiou, Michael
%T Cubyl amides: Novel P2X(7) receptor antagonists.
%B Bioorganic & medicinal chemistry letters
%D 2008
%C United Kingdom
%I Pergamon
%V 18
%N 13
%P 3720-3
%@ 0960-894X
%X Polycyclic amides 2 and 5-9 were successfully synthesised and their lipophilicity profiles were evaluated using reverse-phase HPLC. All synthesised compounds possessed P2X7R antagonistic properties when tested on rat spinal cord microglia cells. Extensive screening for binding to other neuroreceptor subtypes demonstrated their P2X7 selectivity.
%Z FOR Codes: 110313


%0 Journal Article
%A Bennett, Maxwell
%T Dual constraints on synapse formation and regression in schizophrenia: neuregulin, neuroligin, dysbindin, DISC1, MuSK and agrin
%B Australian and New Zealand Journal of Psychiatry
%D 2008
%C Australia
%I Informa Healthcare
%V 42
%N 
%P 662-677
%@ 0004-8674
%X 
%Z FOR Codes: 110319


%0 Book
%A Bennett, Maxwell
%A Hacker, P M S
%T History of Cognitive Neuroscience
%B 
%D 2008
%C United Kingdom
%I Wiley-Blackwell
%V 
%N 
%P 
%@ 9781405181822
%X 
%Z FOR Codes: 110999


%0 Journal Article
%~ PubMed
%A Bennett, M R
%A Farnell, L
%A Gibson, W G
%T Origins of the BOLD changes due to synaptic activity at astrocytes abutting arteriolar smooth muscle.
%B Journal of Theoretical Biology
%D 2008
%C United Kingdom
%I Academic Press Ltd
%V 252
%N 1
%P 123-130
%@ 0022-5193
%X We have recently provided a detailed model that links glutamatergic synaptic activity to volume and blood flow changes in nearby arterioles [Bennett, M.R., Farnell, L., Gibson, W.G., 2008. Origin of blood volume change due to glutamatergic synaptic activity at astrocytes abutting on arteriolar smooth muscle cells. J. Theor. Biol. 250, 172-185]. This neurovascular coupling model is used in the present work to predict changes in deoxyhemoglobin (Hbr) in capillaries, arterioles, venules and veins due to glutamatergic synaptic activity and hence the changes in the blood oxygen level dependent (BOLD) signals recorded by functional magnetic resonance imaging. The model provides a quantitative account of Hbr changes observed in each of the vascular compartments following stimulation of somatosensory cortex and visual cortex and of the BOLD signal following stimulation of motor and visual cortex.
%Z FOR Codes: 110904


%0 Journal Article
%~ PubMed
%A Bennett, Max R
%A Buljan, Vlado
%A Farnell, Les
%A Gibson, William G
%T Purinergic junctional transmission and propagation of calcium waves in cultured spinal cord microglial networks.
%B Purinergic signalling
%D 2008
%C Netherlands
%I Springer Netherlands
%V 4
%N 1
%P 47-59
%@ 1573-9538
%X In order to elucidate the mechanisms of purinergic transmission of calcium (Ca(2 + )) waves between microglial cells, we have employed micro-photolithographic methods to form discrete patterns of microglia that allow quantitative measurements of Ca(2 + ) wave propagation. Microglia were confined to lanes 20-100 [Formula: see text] wide and Ca(2 + ) waves propagated from a point of mechanical stimulation, with a diminution in amplitude, for about 120 [Formula: see text]. The number of cells participating in propagation also decreased over this distance. Ca(2 + ) waves could propagate across a cell-free lane from one microglia lane to another if this distance of separation was less than about 60 [Formula: see text], indicating that propagation involved diffusion of a chemical transmitter. This transmitter was identified as ATP since all Ca(2 + ) wave propagation was blocked by the purinoceptor antagonist suramin, which blocks P2Y(2) and P2Y(12) at relatively low concentrations. Antibodies to P2Y(12) showed these at very high density compared with P2Y(2), indicating a role for P2Y(12) receptors. These observations were quantitatively accounted for by a model in which the main determinants are the diffusion of ATP released from a stimulated microglial cell and differences in the dissociation constant of the purinoceptors on the microglial cells.
%Z FOR Codes: 1116


%0 Journal Article
%A Bennett, Maxwell
%T Stress and anxiety in schizophrenia and depression: glucocorticoids, corticotropin-releasing hormone and synapse regression
%B Australian and New Zealand Journal of Psychiatry
%D 2008
%C Australia
%I Informa Healthcare
%V 42
%N 
%P 995-1002
%@ 0004-8674
%X 
%Z FOR Codes: 110319


%0 Journal Article
%~ PubMed
%A Hickie, Ian
%A Bennett, Maxwell
%T The brain and mind research institute: a unique campus for the integration of clinical and basic neurosciences in Australia.
%B Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists
%D 2008
%C United Kingdom
%I Taylor & Francis Ltd.
%V 16
%N 3
%P 169-172
%@ 1440-1665
%X OBJECTIVE: The aim of this paper is to describe the conceptual and practical development of the Brain and Mind Research Institute (BMRI) at the University of Sydney. METHOD: The key conceptual framework of the BMRI is reviewed and contrasted with other biomedical institutes. The major timelines for appointment of key personnel, development of infrastructure and implementation of clinical capacities are presented. RESULTS: The BMRI has developed over 15000 square metres of designated basic research and clinical space. This is thanks to major investments by the University of Sydney, the Australian and NSW governments and the wider community. CONCLUSION: Amelioration of the burden of disease due to disorders of the brain and mind may result from a conceptual and practical move away from the traditional emphasis on single disorders or narrow research platforms.
%Z FOR Codes: 110319


%0 Journal Article
%~ Isi
%A Bennett, MR
%A Gibson, WG
%A Farnell, L
%T A computational model relating changes in cerebral blood volume to synaptic activity in neurons
%B NEUROCOMPUTING
%D 2007
%C Netherlands
%I Elsevier BV
%V 70
%N 10-12
%P 1674-1679
%@ 0925-2312
%X 
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell R
%T Development of the concept of mind.
%B The Australian and New Zealand journal of psychiatry
%D 2007
%C Australia
%I Blackwell Publishing Asia
%V 41
%N 12
%P 943-56
%@ 1440-1614
%X A short account is given of the development of concepts of soul, mind and brain in order to place in historical context the subject of neuropsychiatry. A selection of primary and secondary historical sources is used to trace development of these concepts. Beginning with the spirits of Animism in the 3rd millennium BC, the Greek invention of the soul and its properties, of thymos (emotion), menos (rage) and nous (intellect) are then traced from the time of Homer, in which the soul does not last the death of the body, to Plato in the 4th century BC who argued that the soul, incorporating the nous (now called mind) is incorporeal and immortal. Plato''s pupil, Aristotle, commented on the impossibility of an incorporeal soul interacting with a corporeal body. He instituted a revolution in the concept of mind. This involved pointing out that ''mind'' is a manner of speaking about our psychological powers as in thinking and remembering. Given that such powers are not a thing the problem does not arise as to the relation between mind and a corporeal body. These ideas of Plato and Aristotle were held by competing scholars and theologians during the next 2000 years. Plato was favoured by many in the Church who could more readily grasp the concept of an immortal and incorporeal soul within the context of Christian thought. Galen established in the 2nd century AD that psychological capacities are associated with the brain, and argued that the fluid-filled ventricles were the part of the brain involved. This argument stood for over 1500 years until the 17th century when Willis, as a consequence of the new blood perfusion techniques developed by Wren following Harvey, showed that blood did not enter the ventricles but the cortex, thereby transferring interest from the ventricles to the cortex. The hegemony of Plato''s ideas was broken about this time by Descartes when he argued that the incorporeal soul does not consist of three parts (thymos, nous and menos) but is solely identical with the mind, which is not just concerned with reasoning but with perception and the senses, indeed identical with consciousness ''taken as everything we are aware of happening within us''. The shadow cast by this concept, necessitating as it does relating the Cartesian mind to the cortex, stretches from the time of Willis, through to the foundation figures of neurophysiology and psychiatry in the early 20th century, namely Sherrington and Kraepelin, and beyond. This history is traced in detail because the Cartesian paradigm provides the main resistance to Kraepelin''s argument that mental illness has biological concomitants. It is argued that the modern tendency to equate the mind with the brain does not illuminate the problem that was solved by Aristotle. The mind is not as either Plato of Descartes would have it, nor is it equivalent to the brain, for talk of the mind is a manner of talking about human psychological powers and their exercise, as in ''mind your step'' (watch where you are going), ''keep that in mind'' (remember it). It is suggested that the history of the concept of mind shows that a human being has a corporeal body and a mind, that is, a range of psychological capacities. It is the role of neuropsychiatry to identify the changes in the corporeal that need to be put aright when these psychological capacities go awry.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Bennett, M R
%A Farnell, L
%A Gibson, W G
%A Dickens, P
%T Mechanisms of calcium sequestration during facilitation at active zones of an amphibian neuromuscular junction.
%B Journal of theoretical biology
%D 2007
%C UK
%I Academic Press
%V 247
%N 2
%P 230-241
%@ 0022-5193
%X The calcium transients (Delta[Ca(2+)](i)) at active zones of amphibian (Bufo marinus) motor-nerve terminals that accompany impulses, visualized using a low-affinity calcium indicator injected into the terminal, are described and the pathways of subsequent sequestration of the residual calcium determined, allowing development of a quantitative model of the sequestering processes. Blocking the endoplasmic reticulum calcium pump with thapsigargin did not affect Delta[Ca(2+)](i) for a single impulse but increased its amplitude during short trains. Blocking the uptake of calcium by mitochondria with CCCP had little effect on Delta[Ca(2+)](i) of a single impulse but greatly increased its amplitude during short trains. This present compartmental model is compatible with our previous Monte Carlo diffusion model of Ca(2+) sequestration during facilitation [Bennett, M.R., Farnell, L., Gibson, W.G., 2004. The facilitated probability of quantal secretion within an array of calcium channels of an active zone at the amphibian neuromuscular junction. Biophys. J. 86(5), 2674-2690], with the single plasmalemma pump in that model now replaced by separate pumps for the plasmalemma and endoplasmic reticulum, as well as the introduction of a mitochondrial uniporter.
%Z FOR Codes: 110905


%0 Journal Article
%~ PubMed
%A Bennett, M R
%A Farnell, L
%A Gibson, W G
%T Origins of blood volume change due to glutamatergic synaptic activity at astrocytes abutting on arteriolar smooth muscle cells.
%B Journal of theoretical biology
%D 2007
%C UK
%I Academic Press
%V 250
%N 1
%P 172-85
%@ 0022-5193
%X The cellular mechanisms that couple activity of glutamatergic synapses with changes in blood flow, measured by a variety of techniques including the BOLD signal, have not previously been modelled. Here we provide such a model, that successfully accounts for the main observed changes in blood flow in both visual cortex and somatosensory cortex following their stimulation by high-contrast drifting grating or by single whisker stimulation, respectively. Coupling from glutamatergic synapses to smooth muscle cells of arterioles is effected by astrocytes releasing epoxyeicosatrienoic acids (EETs) onto them, following glutamate stimulation of the astrocyte. Coupling of EETs to the smooth muscle of arterioles is by means of potassium channels in their membranes, leading to hyperpolarization, relaxation and hence an increase in blood flow. This model predicts a linear increase in blood flow with increasing numbers of activated astrocytes, but a non-linear increase with increasing glutamate release.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Bennett, Maxwell R
%T Synaptic P2X7 receptor regenerative-loop hypothesis for depression.
%B The Australian and New Zealand journal of psychiatry
%D 2007
%C Australia
%I Blackwell Publishing Asia
%V 41
%N 7
%P 563-71
%@ 1440-1614
%X Forty-five years ago the surprising discovery was made, in a Melbourne University laboratory, that peripheral synapses exist that release neither noradrenaline nor acetylcholine. The same laboratory went on to show that one of these then novel transmitters is adenosine 5''-triphosphate (ATP), for which a class of receptors has been dubbed P2X7. Recent linkage studies have shown that the P2X7 gene is associated with major depression and bipolar disorder. This speculative paper considers possible mechanisms that could link polymorphisms in the P2X7 gene with the functioning of neural networks, especially in the hippocampus. A selective review of the neurobiological literature on the location and function of the P2X7 receptor at synapses and on astrocytes as well as microglial cells was performed in the context of determining viable hypotheses as to the function of these receptors during synaptic transmission in the neural networks of the hippocampus. It is suggested that P2X7 receptors participate in a regenerative loop at central glutamatergic synapses. In this loop glutamate-evoked release of ATP from both astrocytes and microglia cells, as well as ATP derived from an autocatalytic release from astrocytes, provides purines that can act on presynaptic P2X7 purinergic receptors. This increases glutamate release to further the amount of ATP at the synapse, leading to a new functional state of the neural network in which the synapse participates. This synaptic ATP can also act on microglia P2X7 receptors to release the cytokine tumour necrosis factor-alpha (TNF-alpha), as can glutamate, with this TNF-alpha acting on the post-synaptic neuronal membrane to increase glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors there. As synaptic ATP and glutamate are maintained by the regenerative loop they provide a sustained release of TNF-alpha, and therefore of AMPA receptor enhancement, increasing synaptic efficacy, and so contributing to the new functional state of the neural network. Infections can change this state by activating toll-like (TOL) receptors on the microglia concomitantly with their P2X7 receptor activation by the regenerative loop, thereby releasing the cytokine interleukin-1beta, which decreases the AMPA receptors in the neural membrane, so decreasing synaptic efficacy and changing the functional state of the neural network in which the synapse resides. Polymorphisms in the P2X7 gene that modify operation of the regenerative loop or the release of cytokines, as can infections, change the functional state of neural networks, which may then lead to vulnerability to mood disorders.
%Z FOR Codes: 110903