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

Mice deficient in the microtubule stabilizing protein STOP (stable tubule only polypeptide) show synaptic plasticity anomalies in hippocampus, dopamine hyper-reactivity in the limbic system and severe behavioral deficits. Some of these disturbances are alleviated by long-term antipsychotic treatment. Therefore, this mouse line represents a pertinent model for some aspects of schizophrenia symptomatology. Numerous data support dysfunction of nicotinic neurotransmission in schizophrenia and epidemiological studies show increased tobacco use in schizophrenic patients, in whom nicotine has been reported to improve cognitive deficits and impairment in sensory gating. In this study, we examined potential alterations in cholinergic (ACh) and nicotinic components and functions in STOP mutant mice. STOP KO mice displayed no variation of the density of ACh esterase and beta2* nicotinic receptors (nAChRs), large reductions in the density of vesicular ACh transporter and alpha6* nAChRs and marked increases in the density of alpha7 nAChRs, in some brain areas. STOP KO mice were hypersensitive to the stimulating locomotor effect of nicotine and, interestingly, their impaired performance in learning the cued version of the water maze were improved by administration of the preferential alpha7 nAChR agonist choline. Altogether, our data show that the deletion of the ubiquitous STOP protein elicited restricted alterations in ACh components. They also suggest that nicotinic neurotransmission can be deficient in STOP KO mice and that mutant mice can represent a meaningful model to study some nicotinic dysfunctions and therapeutic treatments.
 ...
PMID:Sustained increase of alpha7 nicotinic receptors and choline-induced improvement of learning deficit in STOP knock-out mice. 1751 60

The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.
 ...
PMID:Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission. 2214 79

Ligands for epidermal growth factor (EGF) receptor (ErbB1), such as EGF, transforming growth factor alpha (TGFalpha), and epiregulin, are enriched in body fluids and blood and regulate development of various peripheral organs. It remains however how such circulating polypeptide growth factors influence brain development and function. Here, we performed peripheral injections of TGFalpha and epiregulin to mouse neonates and evaluated immediate physical and neurochemical development and later behavioral consequences. Subcutaneous administration of TGFalpha and epiregulin increased phosphorylation of brain ErbB1, suggesting their effects on brain development. Repeated their injections similarly enhanced physical development of eyelid opening and tooth eruption during early postnatal stage and resulted in abnormal behavioral traits in the adult stage. Acoustic startle responses of mice treated with these growth factors as neonates were enhanced and prepulse inhibition was decreased without an apparent correlation between prepulse inhibition level and startle intensity. Locomotor activity and fear-learning performance with tone and context cues were not altered, however. These results suggest that circulating ErbB1 ligands in the periphery of neonates have some common influences on later behavioral traits. Abnormal ErbB1 ligand production at neonatal and potentially prenatal stages might therefore associate with neurodevelopmental disorders such as schizophrenia.
 ...
PMID:Common behavioral influences of the ErbB1 ligands transforming growth factor alpha and epiregulin administered to mouse neonates. 1831 47

The neuregulins are a family of polypeptide factors implicated in a wide range of neurological and psychiatric disorders including multiple sclerosis, schizophrenia, and Alzheimer's disease. Many alternatively-spliced forms of the NRG1 gene are released as soluble factors that can diffuse to near and distant sites within the nervous system where they can accumulate through binding to highly specific heparan-sulfate proteoglycans in the extracellular matrix. Here we have determined the sites of synthesis and accumulation of heparin-binding neuregulin forms in human neocortex, white matter, cerebral spinal fluid, and serum by immunostaining and measurement of neuregulin activity. While neuregulin precursors are expressed predominately within cortical neurons, soluble neuregulin accumulates preferentially on the surface of white matter astrocytes. Consistently, neuregulin activity can be released from the extracellular matrix of human brain by protease treatment. Neuregulin activity is also detectable in human cerebral spinal fluid where its expression appears to be altered in neuronal disorders. While cerebral spinal fluid neuregulin levels were unaltered in patients with multiple sclerosis, they were slightly reduced in amyotrophic lateral sclerosis and Parkinson's disease (p<0.15), but significantly increased in Alzheimer's disease (p<0.01). While not detected in human serum, a novel neuregulin antagonist activity was identified in human serum that could have prevented its detection. These results suggest that human neuregulin is selectively targeted from cortical neurons to white matter extracellular matrix where it exists in steady-state equilibrium with cerebral spinal fluid where it has the potential to serve as a biological marker in human neuronal disorders.
 ...
PMID:Differential distribution of neuregulin in human brain and spinal fluid. 1915 Apr 38

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1) is a neuropeptide with neurotransmission modulating activity. The associations of the PACAP gene with schizophrenia and hippocampal volume have been reported. We recently reported depression-like behavior in the forced swimming test in PACAP deficient mice. Here we examined a possible association between the PACAP gene and major depressive disorder (MDD) in 637 patients and 967 controls and found that a genetic variant in the gene was associated with MDD. The present results suggest that PACAP signaling might contribute to the pathogenesis of MDD.
 ...
PMID:Possible association between the pituitary adenylate cyclase-activating polypeptide (PACAP) gene and major depressive disorder. 1991 36

STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.
 ...
PMID:Nitric oxide synthase mediates the ability of darbepoetin alpha to improve the cognitive performance of STOP null mice. 2232 5

The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia.
 ...
PMID:Replication study of association between ADCYAP1 gene polymorphisms and schizophrenia. 2041 43

The deletion of microtubule-associated protein stable tubule only polypeptide (STOP) leads to neuroanatomical, biochemical and severe behavioral alterations in mice, partly alleviated by antipsychotics. Therefore, STOP knockout (KO) mice have been proposed as a model of some schizophrenia-like symptoms. Preliminary data showed decreased brain serotonin (5-HT) tissue levels in STOP KO mice. As literature data demonstrate various interactions between microtubule-associated proteins and 5-HT, we characterized some features of the serotonergic neurotransmission in STOP KO mice. In the brainstem, mutant mice displayed higher tissue 5-HT levels and in vivo synthesis rate, together with marked increases in 5-HT transporter densities and 5-HT1A autoreceptor levels and electrophysiological sensitivity, without modification of the serotonergic soma number. Conversely, in projection areas, STOP KO mice exhibited lower 5-HT levels and in vivo synthesis rate, associated with severe decreases in 5-HT transporter densities, possibly related to reduced serotonergic terminals. Mutant mice also displayed a deficit of adult hippocampal neurogenesis, probably related to both STOP deletion and 5-HT depletion. Finally, STOP KO mice exhibited a reduced anxiety- and, probably, an increased helpness-status, that could be because of the strong imbalance of the serotonin neurotransmission between somas and terminals. Altogether, these data suggested that STOP deletion elicited peculiar 5-HT disconnectivity.
 ...
PMID:The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network. 2214 79

The microtubule-associated Stable Tubulie Only Polypeptide (STOP; also known as MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. The deletion of STOP in mice leads to severe disorders reminiscent of several schizophrenia-like symptoms, which are also associated with differential alterations of the serotonergic tone in somas versus terminals. In STOP knockout (KO) compared with wild-type mice, serotonin (5-HT) markers are found to be markedly accumulated in the raphe nuclei and, in contrast, deeply depleted in all serotonergic projection areas. In the present study, we carefully examined whether the 5-HT imbalance would lead to behavioral consequences evocative of mood and/or cognitive disorders. We showed that STOP KO mice exhibited depression-like behavior, associated with a decreased anxiety-status in validated paradigms. In addition, although STOP KO mice had a preserved very short-term memory, they failed to perform well in all other learning and memory tasks. We also showed that STOP KO mice exhibited regional imbalance of the norepinephrine tone as observed for 5-HT. As a consequence, mutant mice were hypersensitive to acute antidepressants with different selectivity. Altogether, these data indicate that the deletion of STOP protein in mice caused deep alterations in mood and cognitive performances and that STOP protein might have a crucial role in the 5-HT and norepinephrine networks development.
 ...
PMID:The deletion of STOP/MAP6 protein in mice triggers highly altered mood and impaired cognitive performances. 2214 79

Over the past century, the polypeptide oxytocin has played an important role in medicine with major highlights including the identification of its involvement in parturition and the milk let-down reflex. Oxytocin is now implicated in an extensive range of psychological phenomena including reward and memory processes and has been investigated as a treatment for several psychiatric disorders including addiction, anxiety, autism, and schizophrenia. In this review, we first provide an historical overview of oxytocin and describe key aspects of its physiological activity. We then outline some pharmacological limitations in this field of research before highlighting the role of oxytocin in a wide range of behavioral and neuronal processes. Finally, we review evidence for a modulatory role of oxytocin with regard to psychostimulant effects. Key findings suggest that oxytocin attenuates a broad number of cocaine and methamphetamine induced behaviors and associated neuronal activity in rodents. Evidence also outlines a role for oxytocin in the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in both rodents and humans. Clinical trials should now investigate the effectiveness of oxytocin as a novel intervention for psychostimulant addiction and should aim to determine its specific role in the therapeutic properties of MDMA that are currently being investigated.
 ...
PMID:A brief history of oxytocin and its role in modulating psychostimulant effects. 2334 54


<< Previous 1 2 3 4 5 Next >>