Glutamatergic Synaptic Dysregulation in Schizophrenia: Therapeutic Implications

Coyle, Joseph T.; Basu, Alo C.; Benneyworth, Michael A.; Balu, Darrick T.; Konopaske, Glenn

doi:10.1007/978-3-642-25758-2_10

Cited by 157 publications

(106 citation statements)

References 214 publications

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“…25 This is in line with the fact that administration of sub-anesthetic doses of NMDA receptor antagonists, such as ketamine, phencyclidine (''angel dust''), and dizocilpine (also known as MK801), exerts psychotomimetic activity and impairs cognitive processes. 5,24 These effects resemble the positive and negative symptoms of schizophrenia, respectively. In addition, acute treatment with these drugs increases Therefore, an impaired glutamatergic transmission can be involved in pathophysiology of schizophrenia.…”

Section: Glutamatergic Modelsmentioning

confidence: 91%

“…Glutamate is the major excitatory neurotransmitter in the central nervous system and exerts its actions through interaction with the ionotropic receptors for N-methyl-Daspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate, as well as with metabotropic receptors. 24 One important indication that glutamate may play a role in schizophrenia is a decrease in its levels in the cerebrospinal fluid of patients with this disorder. 25 This is in line with the fact that administration of sub-anesthetic doses of NMDA receptor antagonists, such as ketamine, phencyclidine (''angel dust''), and dizocilpine (also known as MK801), exerts psychotomimetic activity and impairs cognitive processes.…”

Section: Glutamatergic Modelsmentioning

confidence: 99%

“…In addition, acute treatment with these drugs increases Therefore, an impaired glutamatergic transmission can be involved in pathophysiology of schizophrenia. 24,28 As with dopamine, pharmacological models based on the glutamatergic hypothesis have been established, consisting of the blockade of NMDA-receptors.…”

Section: Glutamatergic Modelsmentioning

confidence: 99%

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Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

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Section: Glutamatergic Modelsmentioning

confidence: 91%

Section: Glutamatergic Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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“…Although the current medications for schizophrenia, which mainly block dopamine D2 receptors, are relatively effective in managing the psychosis, they are ineffective in treating the cognitive deficits and negative symptoms (71). These deficits are the most enduring and correlate with the degree of cortical atrophy.…”

Section: −/−mentioning

confidence: 99%

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Balu

Puhl

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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196

201

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Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

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“…Microglia also regulate adult neurogenesis, refine neuronal circuitry and drive oligodendrocyte differentiation during CNS remyelination [13][14][15]. Considering abnormalities in synaptic regulation, neuroplastic changes and neurogenesis have been implicated in the pathology of psychotic disorders [16][17][18]. Microglia-neuron crosstalk [19] may be a focus of future studies on psychiatric disorders.…”

Section: Sakai Et Al / Microglial Gene Expression Alterations In mentioning

confidence: 99%

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

Sakai

Takahashi

et al. 2016

NIB

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Abstract.As recent studies have shown that microglia play a key role in inflammation and immunological challenges as well as have broader roles in synaptic modulation in the brain, studies on psychiatric disorders have increasingly focused on microglia. Microglial abnormalities have consistently been observed in psychiatric postmortem brain studies, including altered microglial activation and changes in the protein and mRNA expression levels of microglial marker molecules, such as major histocompatibility complex, class II, DR (HLA-DR), complement receptor type 3 (CD11b), ionized calcium binding adaptor molecule 1 (IBA-1), macrosialin (CD68) and glucose transporter type 5 (GLUT5). Microglial abnormalities have also been observed in positron emission tomography (PET) studies. Recent advances in omics-based microglial gene expression profiling of psychiatric brains may elucidate microglial involvement in the pathogeneses of psychiatric disorders. In the present paper, we review the current status of research on expression profiling of microglia-relevant molecules in psychiatric postmortem and imaging studies and we discuss future research directions.

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Glutamatergic Synaptic Dysregulation in Schizophrenia: Therapeutic Implications

Cited by 157 publications

References 214 publications

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

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