Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chandelier neurons are a subset of parvalbumin containing cortical interneurons characterised by their preferential targeting of the axon initial segments of pyramidal neurons. They have been the focus of recent interest after evidence that the arrays of boutons are reduced in the prefrontal cortex of schizophrenic patients, post mortem. Since one chandelier neuron may innervate the axon initial segments of several hundred pyramidal neurons, it is hypothesized that their special connectivity might facilitate synchronisation of cortical outputs and play a key role in working memory. Disruption in their function is therefore thought to play a potentially important role in cortically associated symptoms of schizophrenia. Using the isolation rearing animal model of schizophrenia, we examined immunolabelling for GABA-transporter 1, a marker of chandelier cartridges. We show that the numbers of arrays of chandelier axons are reduced by 36% in the ventral prelimbic cortex of isolation-reared rats, compared with their socially-housed litter mates. This mimics findings in the PFC of schizophrenic patients where GAT-1-positive cartridges are reduced by 40% and is the first study to demonstrate changes in chandelier cartridges in an animal model of schizophrenia.
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PMID:Chandelier cartridges in the prefrontal cortex are reduced in isolation reared rats. 1851 13

Alterations in gamma-frequency oscillations are implicated in psychiatric disorders, and polymorphisms in NRG-1 and ERBB4, genes encoding Neuregulin-1 (NRG-1) and one of its receptors, designated ErbB4, are associated with schizophrenia. Here we show that NRG-1 selectively increases the power of kainate-induced, but not carbachol-induced, gamma oscillations in acute hippocampal slices. NRG-1beta is more effective than NRG-1alpha, a splice variant with lower affinity for ErbB receptors, and neither isoform affects the network activity without prior induction of gamma oscillations. NRG-1beta dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 +/- 496%) and mice (710 +/- 299%). These effects of NRG-1beta are blocked by PD158780, a pan-specific antagonist of ErbB receptors, and are mediated specifically via ErbB4 receptors, because mice harboring a targeted mutation of ErbB4 do not respond to NRG-1. Moreover, we demonstrate that 50% of gamma-amino butyric acidergic parvalbumin (PV)-positive interneurons, which heavily contribute to the generation of gamma oscillations, express ErbB4 receptors. Importantly, both the number of PV-immunoreactive interneurons (-31%) and the power of kainate-induced gamma oscillations (-60%) are reduced in ErbB4 knockout mice. This study provides the first plausible link between NRG-1/ErbB4 signaling and rhythmic network activity that may be altered in persons with schizophrenia.
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PMID:Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. 1863 42

A sub-chronic administration of phencyclidine to the rat brings about enduring pathophysiological and cognitive changes that resemble some features of schizophrenia. The present study aimed to determine whether the behavioural consequence of this phencyclidine regime extends to a long-term disruption of social interaction that might provide a parallel with some negative symptoms of the disease. Rats were treated with phencyclidine (2mg/kg bi-daily for 1 week) or vehicle followed by a drug-free period. Social interaction was assessed 24h, 1 week, 3 weeks and 6 weeks post-treatment. A long-lasting disturbance of social behaviour was observed in the phencyclidine group, namely more contact and non-contact interaction with an unfamiliar target rat at all time points. Six weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and dentate gyrus regions. These results show that sub-chronic phencyclidine produces long-lasting disruptions in social interaction that, however, do not model the social withdrawal seen in patients with schizophrenia. These disturbances of social behaviour may be associated with concurrent pathophysiological brain changes.
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PMID:Disturbances in social interaction occur along with pathophysiological deficits following sub-chronic phencyclidine administration in the rat. 1870 51

Perinatal phencyclidine (PCP) treatment has been used to model brain pathological processes that may be present in schizophrenia such as increased apoptosis during early brain development, and long-term alterations in expression of parvalbumin-containing interneurons and glutamatergic N-methyl-D-aspartate (NMDA) receptors. We report that this treatment also affects receptor expression of another excitatory neurotransmitter receptor, the muscarinic receptor. Female rat pups received injections of the NMDA receptor antagonist PCP (10 mg/kg, s.c.) or saline on postnatal days (PN)7, 9 and 11. [3H]Pirenzepine binding to M1/4 receptors was examined at four time-points (PN12, 18, 32 and 96) following treatment cessation. Significant effects of treatment on [3H]pirenzepine binding were evident immediately after treatment cessation with a decrease in PCP-treated rats at PN12 in the prefrontal cortex (-24%, p<0.05) and hippocampus (-19%, p<0.05). After this initial decrease, binding subsequently increased to 47% above control levels in the prefrontal cortex of adolescent animals, which remained elevated in adulthood (+10%, p<0.05), while in the hippocampus there was a trend towards increased binding in adolescent animals and no change thereafter. This work adds to findings demonstrating that perinatal PCP exposure leads to long-term imbalance of excitatory and inhibitory neurotransmitter systems, supporting its relevance as a developmental model of schizophrenia pathology. Alterations in muscarinic receptor expression may contribute specifically to the cognitive impairments reported to occur after perinatal NMDA receptor antagonist treatment.
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PMID:Perinatal PCP treatment alters the developmental expression of prefrontal and hippocampal muscarinic receptors. 1894 Feb 25

A small experimental cryolesion to the right parietal cortex of juvenile mice causes late-onset global brain atrophy with memory impairments, reminiscent of cognitive decline, and progressive brain matter loss in schizophrenia. However, the cellular events underlying this global neurodegeneration are not understood. Here we show, based on comprehensive stereological analysis, that early unilateral lesion causes immediate and lasting bilateral increase in the number of microglia in cingulate cortex and hippocampus, consistent with a chronic low-grade inflammatory process. Whereas the total number of neurons and astrocytes in these brain regions remain unaltered, pointing to a non- gliotic neurodegeneration (as seen in schizophrenia), the subgroup of parvalbumin-positive inhibitory GABAergic interneurons is increased bilaterally in the hippocampus, as is the expression of the GABA-synthesizing enzyme GAD67. Moreover, unilateral parietal lesion causes a decrease in the expression of synapsin1, suggesting impairment of presynaptic functions/neuroplasticity. Reduced expression of the myelin protein cyclic nucleotide phosphodiesterase, reflecting a reduction of oligodendrocytes, may further contribute to the observed brain atrophy. Remarkably, early intervention with recombinant human erythropoietin (EPO), a hematopoietic growth factor with multifaceted neuroprotective properties (intraperitoneal injection of 5000 IU/kg body weight every other day for 3 weeks), prevented all these neurodegenerative changes. To conclude, unilateral parietal lesion of juvenile mice induces a non- gliotic neurodegenerative process, susceptible to early EPO treatment. Although the detailed mechanisms remain to be defined, these profound EPO effects open new ways for prophylaxis and therapy of neuropsychiatric diseases, e.g. schizophrenia.
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PMID:Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion. 1898 36

Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence, suggesting that early insults can have delayed consequences. Many of these behaviors depend on the prefrontal cortex (PFC), and we have reported that PFC pyramidal neurons of adult rats with an NVHL respond to stimulation of the ventral tegmental area with an increase in firing instead of the characteristic decrease. As the dopamine modulation of cortical interneurons matures during adolescence, these findings raise the possibility that maturation of local inhibitory circuits within the PFC may have been altered in NVHL rats. Here, we assessed the state of PFC interneurons in NVHL rats with in situ hybridization measures of the mRNAs for the calcium binding protein parvalbumin (PV) and the GABA synthesizing enzyme GAD(67), as well as with electrophysiological measures of interneuron function. Although no differences were observed with PV or GAD(67), whole-cell recordings in slices revealed abnormal responses to the D(2) agonist quinpirole in interneurons from NVHL rats. The loss of D(2) modulation of local inhibition in slices from NVHL rats was also evident in the absence of a lasting component in the D(2) attenuation of excitatory synaptic responses in pyramidal neurons, which in sham treated rats was picrotoxin sensitive. The results suggest that the neonatal lesion causes improper maturation, but not loss, of PFC interneurons during adolescence, a finding consistent with current interpretations of imaging data in schizophrenia that suggest a hyperactive, "noisy" cortex underlying dysfunction in the PFC and other cortical areas.
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PMID:A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. 1903 62

Studies into the pathophysiology of schizophrenia have consistently demonstrated a dysfunction of dopamine (DA) system regulation in this disorder. This includes hyper-responsivity to DA agonists, the therapeutic efficacy of DA antagonists, and augmented striatal DA release in response to amphetamine. Nonetheless, there is little evidence for a pathological alteration with the DA system itself in schizophrenia. Instead, it is suggested that the disturbance lies in the manner by which the DA system is regulated. Recently, rodent models of schizophrenia have been advanced based on developmental disruption that recapitulates many of the symptoms observed in human schizophrenia patients. We found that administration of the mitotoxin methylazoxymethanol acetate (MAM) to rats at gestational day 17 leads to adult rats that exhibit neuroanatomical, pharmacological, and behavioral characteristics consistent with schizophrenia. These rats also exhibit hyperactivity within the ventral subiculum of the hippocampus that corresponds to a loss of parvalbumin-containing interneurons. This hyperactivity causes an increase in the population activity of the DA neurons (i.e., more DA neurons are firing spontaneously), thus increasing the responsivity of the DA system to stimuli. When the ventral subiculum is inactivated, DA neuron population activity is restored to baseline, and the hyper-responsivity to amphetamine is normalized to that observed in control rats. These findings demonstrate a direct link between the hippocampal pathophysiology, interneuronal alterations, and hyperdopaminergic state observed in the schizophrenia patient. Moreover, this suggests an alternate pharmacotherapeutic approach based on the normalization of hippocampal activity in the treatment of schizophrenia in humans.
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PMID:Hippocampal dysfunction and disruption of dopamine system regulation in an animal model of schizophrenia. 1907 17

Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.
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PMID:Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. 1909 84

The core features of schizophrenia include deficits in cognitive processes, such as attention and working memory, subserved by the prefrontal cortex (PFC). These deficits are believed to involve deficient neurotransmission through NMDA receptors, particularly on parvalbumin-containing interneurons, and administration of the NMDA-antagonist phencyclidine (PCP) in rodents is a well validated model of such cognitive deficits. Here we show that repeated PCP treatment (10 mg/kg/day for 10 days) decreased the expression of parvalbumin and synaptophysin mRNA in the mouse PFC, which corresponds to changes seen in patients with schizophrenia. In addition, PCP increased the basal mRNA expression in the PFC of the activity-regulated cytoskeleton-associated protein (Arc), a molecule involved in synaptic plasticity. These molecular changes produced by PCP were accompanied by a behavioral impairment as determined in a modified Y-maze test. Polymorphisms in the alpha(7) nicotinic acetylcholine receptor (nAChR) gene have been linked to schizophrenia. Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP. Importantly, repeated co-administration of SSR180711 (3 mg/kg) with PCP prevented both the changes in parvalbumin, synaptophysin, and Arc mRNA expression in the PFC, and the behavioral impairment induced by PCP. These results are the first to demonstrate prevention of the deleterious effects induced by repeated PCP treatment. The behavioral and molecular effects of alpha(7) nAChR agonism in this model, particularly the prevention of a decline in parvalbumin mRNA expression, suggest an involvement of the alpha(7) nAChR not only in the symptomatic relief, but also the pathophysiology, of schizophrenia.
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PMID:alpha(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment. 1923 18

Decreased GABAergic signaling is among the more robust pathologies observed postmortem in schizophrenia; however, the functional consequences of this deficit are still largely unknown. Here, we demonstrate, in a verified animal model of schizophrenia, that a reduced expression of parvalbumin (PV)-containing interneurons is correlated with a reduction in coordinated neuronal activity during task performance in freely moving rats. More specifically, methylazoxymethanol acetate (MAM)-treated rats display a decreased density of parvalbumin-positive interneurons throughout the medial prefrontal cortex (mPFC) and ventral (but not dorsal) subiculum of the hippocampus. Furthermore, the reduction in interneuron functionality is correlated with a significantly reduced gamma-band response to a conditioned tone during a latent inhibition paradigm. Finally, deficits in mPFC and ventral hippocampal oscillatory activity are associated with an impaired behavioral expression of latent inhibition in MAM-treated rats. Thus, we propose that a decrease in intrinsic GABAergic signaling may be responsible, at least in part, for the prefrontal and hippocampal hypofunctionality observed during task performance, which is consistently observed in animal models as well as in schizophrenia in humans. In addition, a deficit in intrinsic GABAergic signaling may be the origin of the hippocampal hyperactivity purported to underlie the dopamine dysfunction in psychosis. Such information is central to gaining a better understanding of the disease pathophysiology and alternate pharmacotherapeutic approaches.
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PMID:A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. 1924 11


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