Rina Murai

Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

RationaleCognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.ObjectivesIn this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.Materials and methodsMice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.ResultsSingle (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D1 receptor antagonist, SCH23390, and a serotonin 5-HT1A receptor antagonist, WAY100635; however, co-treatment with a D2 receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.ConclusionsThese results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D1 and serotonin 5-HT1A receptors.

Diabetic neuropathies in brain are induced by deficiency of BDNF.

Diabetes is known to be one of the risk factors for dementia; however, neuropathic changes in the brain of patients with the disease have not been completely revealed. So in the present study, we investigated the brain function of rats with diabetes induced by streptozotocin (STZ), one of the most commonly used animal models for diabetes. In the diabetic rats, immediately working memory performance was impaired in the Y-maze task and neuronal cytoskeleton proteins such as calbindin, synaptophysin, and syntaxin were reduced. Furthermore, morphological observation by Golgi staining showed a decrease in the number of basal dendrites and abnormality of spine structure. Next, we measured the content of brain-derived neurotrophic factor (BDNF) in the diabetic brain, because BDNF is one of the essential proteins for the maintenance of neuronal functions including synapse function and neuronal transmissions. In the diabetic brains, both protein and mRNA levels of BDNF were severely reduced. These results suggest that, in diabetes, synapse dysfunction is, at least in part, caused by a failure of BDNF synthesis in the brain.

Brain-Derived Neurotrophic Factor Participates in Determination of Neuronal Laminar Fate in the Developing Mouse Cerebral Cortex

Lamina formation in the developing cerebral cortex requires precisely regulated generation and migration of the cortical progenitor cells. To test the possible involvement of brain-derived neurotrophic factor (BDNF) in the formation of the cortical lamina, we investigated the effects of BDNF protein and anti-BDNF antibody separately administered into the telencephalic ventricular space of 13.5-d-old mouse embryos. BDNF altered the position, gene-expression properties, and projections of neurons otherwise destined for layer IV to those of neurons for the deeper layers, V and VI, of the cerebral cortex, whereas anti-BDNF antibody changed some of those of neurons of upper layers II/III. Additional analysis revealed that BDNF altered the laminar fate of neurons only if their parent progenitor cells were exposed to it at approximately S-phase and that it hastened the timing of the withdrawal of their daughter neurons from the ventricular proliferating pool by accelerating the completion of S-phase, downregulation of the Pax6 (paired box gene 6) expression, an essential transcription factor for generation of the upper layer neurons, and interkinetic nuclear migration of cortical progenitors in the ventricular zone. These observations suggest that BDNF participates in the processes forming the neuronal laminas in the developing cerebral cortex. BDNF can therefore be counted as one of the key extrinsic factors that regulate the laminar fate of cortical neurons.

Animal model of schizophrenia : Dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine

Abstract:  In humans, phencyclidine (PCP), a noncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, reproduces a schizophrenia‐like psychosis such as positive/negative symptoms and cognitive deficits. PCP (10 mg/kg/day for 14 days)‐treated mice exhibit the enhanced immobility in a forced swimming test as indexes of negative symptoms and impairment of latent learning in a water finding test as indexes of cognitive deficits. These behavioral deficits remain after withdrawal from repeated PCP treatment and are attenuated by atypical antipsychotics, but not by typical antipsychotics. Since it has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia, we investigated an involvement of glutamatergic system in emotional and cognitive deficits in mice treated with PCP repeatedly. Ca2+/calmodulin kinase II (CaMKII) is markedly phosphorylated after the forced swimming test and the training trial of water finding test in the prefrontal cortex of saline‐treated mice but not PCP‐treated mice. Facilitation of NMDA receptor function by NMDA receptor glycine‐site agonists such as D‐cycloserine and glycine is effective on the abnormal intracellular signaling, and emotional and cognitive deficits in mice treated with PCP repeatedly. The repeated PCP treatment impaired NMDA receptor function and decreased levels of spontaneous extracellular glutamate in the prefrontal cortex, indicating that the repeated PCP treatment impairs both pre‐ and postsynaptic glutamate transmissions. Our findings suggest that abnormal NMDA receptor signaling is involved in the emotional and cognitive deficits in mice treated with PCP repeatedly. Our PCP‐treated mice would be a useful model for studying the effect of antipsychotics on emotional and cognitive deficits in schizophrenia.

Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: implications for abnormalities of glutamate release and NMDA-CaMKII signaling.

In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the enhancement of immobility (emotional deficit) in a forced swimming test in mice treated with phencyclidine (PCP: 10mg/kg/day for 14 days) repeatedly, which is regarded as an animal model for negative symptoms. A decrease in spontaneous extracellular glutamate release and increase in levels of the glutamate transporter GLAST, were observed in the prefrontal cortex (PFC) of PCP-treated mice, compared to saline-treated mice. NMDA receptor subunit 1 (NR1) and Ca(2+)/calmoduline kinase II (CaMKII) were markedly activated in the PFC of saline-treated mice, but not PCP-treated mice, immediately after the forced swimming test. The facilitation of the function of NMDA receptors by d-cycloserine (30mg/kg i.p.), an NMDA receptor glycine-site partial agonist, reversed the enhancement of immobility in the forced swimming test and impairment of CaMKII activation in the PCP-treated mice. Microinjection of dl-threo-beta-benzyloxyaspartate (10nmol/site/bilaterally), a potent blocker of glutamate transporters, into the PFC of PCP-treated mice also had an attenuating effect. In addition, activation of glial cells and a decrease of neuronal cell size were observed in the PFC of PCP-treated mice. These results suggest that repeated PCP treatment disrupts pre- and post-synaptic glutamatergic neurotransmission and induces morphological changes in the PFC and that such changes cause the emotional deficits exhibited in PCP-treated mice.

Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging

Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging.

The Extensive Nitration of Neurofilament Light Chain in the Hippocampus Is Associated with the Cognitive Impairment Induced by Amyloid β in Mice

Tyrosine nitration of proteins at an extensive level is widely associated with the cognitive pathology induced by amyloid β peptide (Aβ). However, the precise identity and explicit consequences of protein nitration have scarcely been addressed. In this study, we examined the detectable nitration of proteins in the hippocampus of mice with cognitive impairment (day 5) induced by the i.c.v. injection of Aβ25–35 (day 0). The intensity of the nitration of proteins was inversely associated with the level of recognition memory in mice. The detectable tyrosine nitrations were revealed in proteins with a single size of approximately 70 kDa. The specific nitrated proteins at this size were identified using the liquid chromatography/mass spectrometry/mass spectrometry analysis and immunodetection methods. Intense nitration of the neurofilament light chain (NFL) was observed. The increased nitration of NFL was associated with its serine hyperphosphorylation and weak interaction with the nuclear distribution element-like, a protein essential for the stable assembly of neurofilaments. No changes in cell numbers in the hippocampus were found (day 5) in mice that received Aβ25–35 injections. These findings suggested that extensive nitration of NFL is associated with the Aβ-induced impairment of recognition memory in mice.

Effects of single and repeated administration of methamphetamine or morphine on neuroglycan C gene expression in the rat brain.

The rearrangement of neural networks associated with the behavioural sensitization and tolerance induced by psychostimulants is poorly understood. We have investigated the effects of repeated administration of methamphetamine (chronic MAP), which induces behavioural sensitization, or morphine (chronic morphine), which induces tolerance to its antinociceptive effect, on the mRNA levels of neural network-related genes in the rat brain. A gene of special interest was that for neuroglycan C (NGC), a neural tissue-specific transmembrane chondroitin sulphate proteoglycan. Single MAP (acute MAP) administration significantly decreased NGC mRNA levels in the frontal cortex, ventral tegmental area (VTA), and amygdala compared to vehicle-treated groups. Repeated MAP (chronic MAP) administration significantly increased NGC mRNA levels in the frontal cortex, nucleus accumbens (NAc), striatum, hippocampus, VTA, and amygdala compared to acute MAP treatment. Single morphine (acute morphine) administration significantly increased NGC mRNA levels in the NAc, striatum, hippocampus, VTA, and amygdala compared to vehicle-treated groups. Chronic morphine administration significantly decreased NGC mRNA levels in the NAc, striatum, VTA, and amygdala compared to acute treatment. In addition, the NGC protein level in the NAc was increased after chronic MAP and acute morphine treatment. Dopamine and opioid receptor antagonists attenuated the effect of MAP and morphine respectively on NGC mRNA levels. These results suggest that the sensitization to MAP is associated with up-regulation of NGC gene expression, while the tolerance to the morphine-induced analgesic effect is associated with the down-regulation of NGC gene expression.