Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Tonic excitation or inhibition is set by GABAA conductance in hippocampal interneurons

Inhibition is a physiological process that decreases the probability of a neuron generating an action potential. The two main mechanisms that have been proposed for inhibition are hyperpolarization and shunting. Shunting results from increased membrane conductance, and it reduces the neuron-firing probability. Here we show that ambient GABA, the main inhibitory neurotransmitter in the brain, can excite adult hippocampal interneurons. In these cells, the GABAA current reversal potential is depolarizing, making baseline tonic GABAA conductance excitatory. Increasing the tonic conductance enhances shunting-mediated inhibition, which eventually overpowers the excitation. Such a biphasic change in interneuron firing leads to corresponding changes in the GABAA-mediated synaptic signalling. The described phenomenon suggests that the excitatory or inhibitory actions of the current are set not only by the reversal potential, but also by the conductance

Efficient Physical Embedding of Topologically Complex Information Processing Networks in Brains and Computer Circuits

Nervous systems are information processing networks that evolved by natural selection, whereas very large scale integrated (VLSI) computer circuits have evolved by commercially driven technology development. Here we follow historic intuition that all physical information processing systems will share key organizational properties, such as modularity, that generally confer adaptivity of function. It has long been observed that modular VLSI circuits demonstrate an isometric scaling relationship between the number of processing elements and the number of connections, known as Rent's rule, which is related to the dimensionality of the circuit's interconnect topology and its logical capacity. We show that human brain structural networks, and the nervous system of the nematode C. elegans, also obey Rent's rule, and exhibit some degree of hierarchical modularity. We further show that the estimated Rent exponent of human brain networks, derived from MRI data, can explain the allometric scaling relations between gray and white matter volumes across a wide range of mammalian species, again suggesting that these principles of nervous system design are highly conserved. For each of these fractal modular networks, the dimensionality of the interconnect topology was greater than the 2 or 3 Euclidean dimensions of the space in which it was embedded. This relatively high complexity entailed extra cost in physical wiring: although all networks were economically or cost-efficiently wired they did not strictly minimize wiring costs. Artificial and biological information processing systems both may evolve to optimize a trade-off between physical cost and topological complexity, resulting in the emergence of homologous principles of economical, fractal and modular design across many different kinds of nervous and computational networks

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Metal-metal interactions in binuclear platinum(II) diphosphite complexes. Resonance raman spectra of the 1A1g(dσ*)2 and 3A2u(dσ*pσ) electronic states of Pt2(P2O5H2)4 4-

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Vibrational and electronic spectra of [Pt2(SO4)]2- complexes

The vibrational and electronic spectra of axially ligated sulfate-bridged binuclear platinum complexes ([Pt2(SO4)4L2]n-: L = OH2, DMSO, n = 2; L = Cl, Br, n = 4) have been studied. Raman spectra acquired with near-UV excitation show bands assigned to Pt-O(sulfate) stretching (300-350-cm-1 region) for all complexes, while bands assigned to Pt-Pt and Pt-L stretching are seen for complexes (L = Cl, Br) that display preresonance Raman scattering within intense near-UV absorption bands assigned to the σ(L) → σ*(Pt2) electronic transition. Weaker electronic absorptions are assigned as metal-metal 1(σ→σ*) (near 220 nm for L = OH2, Cl) and dπ → dσ*(Pt2) (350-500 nm). Single-crystal polarized absorption spectra (L = OH2, DMSO) show that the weak absorption system in the 350-500-nm region consists of three x,y-polarized (metal-metal axis) bands and an x,y-polarized band. The L = OH2, Cl complexes show weak emission bands in the 695-750-nm region when excited at 77 K with near-UV light. These emission bands are similar to those observed for [Pt2(HPO4)4L2]n- (L = OH2, n = 2; L = Cl, n = 4) complexes. The emission lifetimes for the sulfate-bridged complexes (450 ± 50 ns, L = OH2; 290 ± 20 ns, L = Cl) are much shorter, and the emission intensities are much weaker, than the corresponding properties of the phosphate-bridged complexes. © 1991 American Chemical Society.link_to_subscribed_fulltex