Stuart R Cobb

Publications (14)59.73 Total impact

• Article: Neurodevelopmental disorders.

  Stuart R Cobb, Ceri H Davies
  Neuropharmacology 02/2013; · 4.81 Impact Factor
• Article: Rett syndrome: from bed to bench.

  Shih-Ming Weng, Mark E S Bailey, Stuart R Cobb
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  ABSTRACT: Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.
  Pediatrics & Neonatology 12/2011; 52(6):309-16. · 0.75 Impact Factor
• Article: Altered apoptotic responses in neurons lacking RhoB GTPase.

  Sara Barberan, Kara McNair, Khalil Iqbal, Nicola C Smith, George C Prendergast, Trevor W Stone, Stuart R Cobb, Brian J Morris
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  ABSTRACT: Caspase 3 activation has been linked to the acute neurotoxic effects of central nervous system damage, as in traumatic brain injury or cerebral ischaemia, and also to the early events leading to long-term neurodegeneration, as in Alzheimer's disease. However, the precise mechanisms activating caspase 3 in neuronal injury are unclear. RhoB is a member of the Rho GTPase family that is dramatically induced by cerebral ischaemia or neurotrauma, both in preclinical models and clinically. In the current study, we tested the hypothesis that RhoB might directly modulate caspase 3 activity and apoptotic or necrotic responses in neurons. Over-expression of RhoB in the NG108-15 neuronal cell line or in cultured corticohippocampal neurons elevated caspase 3 activity without inducing overt toxicity. Cultured corticohippocampal neurons from RhoB knockout mice did not show any differences in sensitivity to a necrotic stimulus - acute calcium ionophore exposure - compared with neurons from wild-type mice. However, corticohippocampal neurons lacking RhoB exhibited a reduction in the degree of DNA fragmentation and caspase 3 activation induced by the apoptotic agent staurosporine, in parallel with increased neuronal survival. Staurosporine induction of caspase 9 activity was also suppressed. RhoB knockout mice showed reduced basal levels of caspase 3 activity in the adult brain. These data directly implicate neuronal RhoB in caspase 3 activation and the initial stages of programmed cell death, and suggest that RhoB may represent an attractive target for therapeutic intervention in conditions involving elevated caspase 3 activity in the central nervous system.
  European Journal of Neuroscience 11/2011; 34(11):1737-46. · 3.63 Impact Factor
• Source

  Available from: Kamal K E Gadalla

  Article: MeCP2 and Rett syndrome: reversibility and potential avenues for therapy.

  Kamal K E Gadalla, Mark E S Bailey, Stuart R Cobb
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  ABSTRACT: Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.
  Biochemical Journal 10/2011; 439(1):1-14. · 4.90 Impact Factor
• Source

  Available from: Ed Bullmore

  Article: Studying synaptic plasticity in the human brain and opportunities for drug discovery.

  Pradeep J Nathan, Stuart R Cobb, Bai Lu, Edward T Bullmore, Ceri H Davies
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  ABSTRACT: Synaptic plasticity is the ability of synaptic connections between neurons to be strengthened or weakened; a process that is central to the information processing within the brain and which plays a particularly important role in enabling higher cognitive processes [1,2]. Its role in disease is becoming increasingly clear across a wide spectrum of CNS disorders. Thus, for example, dysfunctional synaptic plasticity has been reported in neurodegenerative disorders such as Alzheimer's Disease (AD) as well as in schizophrenia and in a range of disorders associated with learning disabilities [3]. Moreover, maladaptive plasticity processes in response to specific external challenges are believed to underlie disorders such as addiction and post-traumatic stress disorder (PTSD). The molecular basis of normal and disease plasticity is rapidly being unravelled such that synaptic plasticity now provides a unique platform from which to launch the hunt for highly innovative drugs to treat CNS disease by either, firstly, rectifying identifiable abnormalities in these processes, or secondly, utilizing these processes as a vehicle to rectify, or bypass, other mechanisms underlying disease. In this respect, recent advances have been made in studying synaptic plasticity in humans at the molecular through to clinical level and these approaches now provide a real opportunity to test synaptic plasticity as a treatment paradigm for a wide variety of CNS disorders.
  Current Opinion in Pharmacology 07/2011; 11(5):540-8. · 6.86 Impact Factor
• Article: A role for RhoB in synaptic plasticity and the regulation of neuronal morphology.

  Kara McNair, Rosemary Spike, Clare Guilding, George C Prendergast, Trevor W Stone, Stuart R Cobb, Brian J Morris
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  ABSTRACT: Actin-rich dendritic spines are the locus of excitatory synaptic transmission and plastic events such as long-term potentiation (LTP). Morphological plasticity of spines accompanies activity-dependent changes in synaptic strength. Several Rho GTPase family members are implicated in regulating neuronal and, in particular, spine structure via actin and the actin-binding protein cofilin. However, despite expression in hippocampus and cortex, its ability to modulate actin-regulatory proteins, and its induction during aging, RhoB has been relatively neglected. We previously demonstrated that LTP is associated with specific RhoB activation. Here, we further examined its role in synaptic function using mice with genetic deletion of the RhoB GTPase (RhoB(-/-) mice). Normal basal synaptic transmission accompanied reduced paired-pulse facilitation and post-tetanic potentiation in the hippocampus of RhoB(-/-) mice. Early phase LTP was significantly reduced in RhoB(-/-) animals, whereas the later phase was unaffected. In wild-type mice (RhoB(+/+)), Western blot analysis of potentiated hippocampus showed significant increases in phosphorylated cofilin relative to nonpotentiated slices, which were dramatically impaired in RhoB(-/-) slices. There was also a deficit in phosphorylated Lim kinase levels in the hippocampus from RhoB(-/-) mice. Morphological analysis suggested that lack of RhoB resulted in increased dendritic branching and decreased spine number. Furthermore, an increase in the proportion of stubby relative to thin spines was observed. Moreover, spines demonstrated increased length along with increased head and neck widths. These data implicate RhoB in cofilin regulation and dendritic and spine morphology, highlighting its importance in synaptic plasticity at a structural and functional level.
  Journal of Neuroscience 03/2010; 30(9):3508-17. · 7.11 Impact Factor
• Article: Time-dependent evolution of tissue markers by MALDI-MS imaging.

  Richard J A Goodwin, Jessica C Dungworth, Stuart R Cobb, Andrew R Pitt
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  ABSTRACT: We have used MALDI-MS imaging (MALDI-MSI) to monitor the time dependent appearance and loss of signals when tissue slices are brought rapidly to room temperature for short to medium periods of time. Sections from mouse brain were cut in a cryostat microtome, placed on a MALDI target and allowed to warm to room temperature for 30 s to 3 h. Sections were then refrozen, fixed by ethanol treatment and analysed by MALDI-MSI. The intensity of a range of markers were seen to vary across the time course, both increasing and decreasing, with the intensity of some markers changing significantly within 30 s and markers also showed tissue location specific evolution. The markers resulting from this autolysis were compared directly to those that evolved in a comparable 16 h on-tissue trypsin digest, and the markers that evolved in the two studies were seen to be substantially different. These changes offer an important additional level of location-dependent information for mapping changes and seeking disease-dependent biomarkers in the tissue. They also indicate that considerable care is required to allow comparison of biomarkers between MALDI-MSI experiments and also has implications for the standard practice of thaw-mounting multiple tissue sections onto MALDI-MS targets.
  Proteomics 09/2008; 8(18):3801-8. · 4.43 Impact Factor
• Article: Proteomics in the study of hippocampal plasticity.

  Stuart R Cobb, Andrew Pitt
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  ABSTRACT: Synaptic plasticity is the dynamic regulation of the strength of synaptic communication between nerve cells. It is central to neuronal development as well as experience-dependent remodeling of the adult nervous system as occurs during memory formation. Aberrant forms of synaptic plasticity also accompany a variety of neurological and psychiatric diseases, and unraveling the biological basis of synaptic plasticity has been a major goal in neurobiology research. The biochemical and structural mechanisms underlying different forms of synaptic plasticity are complex, involving multiple signaling cascades, reconfigurations of structural proteins and the trafficking of synaptic proteins. As such, proteomics should be a valuable tool in dissecting the molecular events underlying normal and disease-related forms of plasticity. In fact, progress in this area has been disappointingly slow. We discuss the particular challenges associated with proteomic interrogation of synaptic plasticity processes and outline ways in which we believe proteomics may advance the field over the next few years. We pay particular attention to technical advances being made in small sample proteomics and the advent of proteomic imaging in studying brain plasticity.
  Expert Review of Proteomics 07/2008; 5(3):393-404. · 3.68 Impact Factor
• Article: Normal electrical properties of hippocampal neurons modelling early Huntington disease pathogenesis.

  Peggy Shelbourne, Edward Coote, Selma Dadak, Stuart R Cobb
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  ABSTRACT: Huntington disease (HD) is a neurodegenerative disorder caused by an unstable and progressive expansion of a CAG trinucleotide repeat tract in the HD gene. Previous studies using truncated forms of the HD gene have shown pronounced deficits in synaptic transmission and plasticity but rather modest changes in intrinsic cellular properties, despite overt pathology. The knock-in mice carrying a 72-80 CAG repeat mutation is an accurate genetic model of early stage HD, displaying a more subtle disease phenotype. To relate full-length HD gene expression and differential polyglutamine expansion with possible pathophysiological changes in salient electrophysiological properties of neurons that may underlie early symptoms of HD, including mood and cognitive impairments, we have conducted whole-cell recordings from hippocampal area CA1 pyramidal cells in Hdh6/Q72 and Hdh4/Q80 knock-in mice. Electrophysiological characterisation of cells obtained from young adult (<4 months) HD mice harbouring an expanded CAG repeat stretch and age-matched wild type (WT) mice revealed no significant differences in any of the active or passive membrane properties investigated. Similar findings, showing a lack of significant differences in cellular electrical properties, were obtained from cells of aged (>18 months) HD mice and WT controls, despite modest levels of repeat length variability demonstrated by single cell PCR. Thus, the current study indicates a lack of overt changes in the electrical membrane properties of pyramidal cells in HD mice accurately modelling early stage HD pathology. Furthermore, together with our previous work, these findings point to a synaptic rather than cellular locus of HD-related pathology.
  Brain Research 04/2007; 1139:226-34. · 2.73 Impact Factor
• Article: Inhibition of Ih reduces epileptiform activity in rodent hippocampal slices.

  Catherine H Gill, Jon T Brown, Nadia Shivji, Sarah C Lappin, Clare Farmer, Andrew Randall, Nicolle C L McNaughton, Stuart R Cobb, Ceri H Davies
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  ABSTRACT: Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels regulate membrane potential, neurotransmitter release, and patterning of synchronized neuronal activity. Currently, there is an intense debate as to whether or not these ion channels play a pro- or anticonvulsant role in vivo. To gain an insight into this question, we have examined how inhibitors of the response mediated by HCN channels (referred to as I(h)) affect epileptiform activity induced in adult hippocampal slices. The archetypal I(h) blocker ZD-7288 produced a concentration-dependent inhibition of both nonsynaptic- (low Ca(2+)/elevated K(+) aCSF) and synaptic- (low Mg(2+) aCSF, elevated K(+) aCSF or convulsant application (bicuculline or pentylenetetrazol)) based epileptiform activities. The IC(50) value for ZD-7288 induced inhibition of epileptiform activity was similar across all forms of epileptiform response and was below concentrations producing nonspecific inhibition of glutamatergic synaptic transmission. Furthermore, capsazepine, which exhibits similar potency to ZD-7288 at inhibiting I(h), failed to inhibit glutamatergic synaptic transmission per se but produced a significant inhibition of bicuculline-induced epileptiform activity. These data suggest that broad spectrum inhibition of I(h) reduces neuronal hyperexcitability in the hippocampus.
  Synapse 05/2006; 59(5):308-16. · 2.94 Impact Factor
• Article: Plasticity-related regulation of the hippocampal proteome.

  Kara McNair, Ceri H Davies, Stuart R Cobb
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  ABSTRACT: Plasticity of glutamatergic synapses is considered to be a pivotal mechanism underlying the ability of the CNS to re-configure its neural circuits. A large number of studies have focused on investigating how individual proteins, biochemical pathways and structural processes alter both the induction and maintenance of synaptic plasticity. However, it is likely that synaptic plasticity involves temporally and spatially coordinated regulation of multiple protein complexes within the activated neural circuit. By using a global proteomics-based approach we have now been able to reveal that highly diverse protein classes exhibit altered expression in response to both the activation of glutamate receptors and the induction of long-term potentiation (LTP) of glutamatergic synaptic strength in the hippocampus; a brain area where plastic synaptic modification is believed to be key to cognitive processes, such as spatial learning. Of the 2946 resolvable protein spots detected in this study, 79 (2.7%) were significantly altered in abundance in response to 100 microM glutamate application (all P < 0.05). The majority (56 out of 79) of these changes were due to the activation of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. Likewise, the induction of LTP was associated with an altered abundance of 2.4% of the detectable proteome during the early (10 min) phase and 1.7% during the late (4 h) phase of its development. Observed changes in temporal and protein class-specific patterns of expression depict a widespread shift from metabolic to structural protein alteration as the plasticity process matures.
  European Journal of Neuroscience 02/2006; 23(2):575-80. · 3.63 Impact Factor
• Article: Cholinergic modulation of hippocampal cells and circuits.

  Stuart R Cobb, Ceri H Davies
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  ABSTRACT: Septo-hippocampal cholinergic fibres ramify extensively throughout the hippocampal formation to release acetylcholine upon a diverse range of muscarinic and nicotinic acetylcholine receptors that are differentially expressed by distinct populations of neurones. The resultant modulation of cellular excitability and synaptic transmission within hippocampal circuits underlies the ability of acetylcholine to influence the dynamic properties of the hippocampal network and results in the emergence of a range of stable oscillatory network states. Recent findings suggest a multitude of actions contribute to the oscillogenic properties of acetylcholine which are principally induced by activation of muscarinic receptors but also regulated through activation of nicotinic receptor subtypes.
  The Journal of Physiology 02/2005; 562(Pt 1):81-8. · 4.72 Impact Factor
• Article: Regulation of muscarinic acetylcholine receptor‐mediated synaptic responses by GABAB receptors in the rat hippocampus

  Robin A. Morton, Nick A. Manuel, Diederick O. Bulters, Stuart R. Cobb, Ceri H. Davies
  The Journal of Physiology 08/2004; 535(3):757 - 766. · 4.72 Impact Factor
• Article: Complex interactions between mGluR1 and mGluR5 shape neuronal network activity in the rat hippocampus.

  Christophe Lanneau, Mark H Harries, Alison M Ray, Stuart R Cobb, Andrew Randall, Ceri H Davies
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  ABSTRACT: Group I metabotropic glutamate receptors (mGluRs) cause increased neuronal excitability that can lead to epileptogenesis and neurodegeneration. Here we have examined how individual members of this subgroup of mGluRs affect synchronised hippocampal synaptic activity under normal and disinhibited conditions similar to those that occur during certain epileptic states. We demonstrate that activation of both mGluR1 and mGluR5 are important in increasing neuronal synaptic excitability by increasing synchrony between cells and driving correlated network activity in circuits that contain, or are devoid of, GABA(A) receptor-mediated synaptic inputs. The precise patterning of activity that occurs is complex and depends upon: (1) the existing pattern of ongoing network activity prior to mGluR activation; and (2) the relative extent of activation of each mGluR subtype. However, mGluR5 appears to be the principal mGluR subtype that initiates bursting activity irrespective of the inhibitory synaptic tone within the neuronal network.
  Neuropharmacology 09/2002; 43(2):131-40. · 4.81 Impact Factor