Brain region networks for the assimilation of new associative memory into a schema.

Alterations in long-range functional connectivity between distinct brain regions are thought to contribute to the encoding of memory. However, little is known about how the activation of an existing network of neocortical and hippocampal regions might support the assimilation of relevant new information into the preexisting knowledge structure or 'schema'. Using functional mapping for expression of plasticity-related immediate early gene products, we sought to identify the long-range functional network of paired-associate memory, and the encoding and assimilation of relevant new paired-associates.

Reversibility of motor dysfunction in the rat model of NGLY1 deficiency.

N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1-/-, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability.

Post-Marketing Surveillance of Fluvoxamine Maleate Used Long-Term in Patients with Social Anxiety Disorder in Japan.

Background: No data on the long-term 'real-world' use of fluvoxamine for the treatment of social anxiety disorder (SAD) in Japanese patients are currently available.

Objective: To evaluate the long-term safety and efficacy of fluvoxamine for SAD in the clinical setting.

Methods: Japanese patients with SAD who initiated treatment with fluvoxamine were enrolled in this 53-week post-marketing survey from 407 institutions nationwide.

Identification of a developmentally-regulated and psychostimulant-inducible novel rat gene mrt3 in the neocortex.

The psychotomimetic effects of stimulant drugs including amphetamines and cocaine are known to change during the postnatal development in humans and experimental animals. To obtain an insight into the molecular basis of the onset of stimulant-induced psychosis, we have explored the gene transcripts that differentially respond to methamphetamine (MAP) in the developing rat brains using a differential cloning technique, the RNA arbitrarily-primed PCR. We identified from the rat neocortex a novel and developmentally regulated MAP-inducible gene mrt3 (MAP responsive transcript 3) that is transcribed to a presumable non-coding RNA of 3.

Targeting kynurenine aminotransferase II in psychiatric diseases: promising effects of an orally active enzyme inhibitor.

Increased brain levels of the tryptophan metabolite kynurenic acid (KYNA) have been linked to cognitive dysfunctions in schizophrenia and other psychiatric diseases. In the rat, local inhibition of kynurenine aminotransferase II (KAT II), the enzyme responsible for the neosynthesis of readily mobilizable KYNA in the brain, leads to a prompt reduction in extracellular KYNA levels, and secondarily induces an increase in extracellular glutamate, dopamine, and acetylcholine levels in several brain areas. Using microdialysis in unanesthetized, adult rats, we now show that the novel, systemically active KAT II inhibitor BFF-816, applied orally at 30 mg/kg in all experiments, mimics the effects of local enzyme inhibition.

Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis.

A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice.

Increasing effects of S-methyl-L-cysteine on the extracellular D-serine concentrations in the rat medial frontal cortex.

In an in vivo dialysis experiment, the intra-medial frontal cortex infusion of a system A and Asc-1 transporter inhibitor, S-methyl-L-cysteine, caused a concentration-dependent increase in the dialysate contents of an endogenous coagonist for the N-methyl-D-aspartate (NMDA) type glutamate receptor, D-serine, in the cortical portion. These results suggest that these neutral amino acid transporters could control the extracellular D-serine signaling in the brain and be a target for the development of a novel threapy for neuropsychiatric disorders with an NMDA receptor dysfunction.

Schema-dependent gene activation and memory encoding in neocortex.

When new learning occurs against the background of established prior knowledge, relevant new information can be assimilated into a schema and thereby expand the knowledge base. An animal model of this important component of memory consolidation reveals that systems memory consolidation can be very fast. In experiments with rats, we found that the hippocampal-dependent learning of new paired associates is associated with a striking up-regulation of immediate early genes in the prelimbic region of the medial prefrontal cortex, and that pharmacological interventions targeted at that area can prevent both new learning and the recall of remotely and even recently consolidated information.

Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.

Context: Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway.

Age dependency of inhibition of alpha7 nicotinic receptors and tonically active N-methyl-D-aspartate receptors by endogenously produced kynurenic acid in the brain.

In the mouse hippocampus normal levels of kynurenic acid (KYNA), a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of L-kynurenine, maintain a degree of tonic inhibition of α7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that α7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 μM) resulted in continuous de novo synthesis of KYNA.

Crystal structure-based selective targeting of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II for cognitive enhancement.

Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(-)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs.

The development- and phencyclidine-regulated induction of synapse-associated protein-97 gene in the rat neocortex.

Using the RNA arbitrarily-primed PCR and the competitive RT-PCR, we have isolated the neocortical transcripts that are upregulated and unchanged in the adult and infant rats, respectively, after a systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP), and found them identical to the synapse-associated protein-97 (SAP97) gene mRNAs. The upregulation of the SAP97 transcripts in the adult neocortex after the acute PCP injection was mimicked by another NMDA antagonist, dizocilpine, but not by the indirect dopamine agonists, methamphetamine and cocaine, a selective D1 receptor antagonist SCH23390, a D2 receptor-preferring antagonist haloperidol and a GABAergic anesthetic pentobarbital. Moreover, the pretreatment with a typical antipsychotic haloperidol failed to antagonize the increased neocortical SAP97 gene expression by PCP.

Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression.

Background: Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors.

On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo.

In the mammalian brain, kynurenine aminotransferase II (KAT II) and kynurenine 3-monooxygenase (KMO), key enzymes of the kynurenine pathway (KP) of tryptophan degradation, form the neuroactive metabolites kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), respectively. Although physically segregated, both enzymes use the pivotal KP metabolite l-kynurenine as a substrate. We studied the functional consequences of this cellular compartmentalization in vivo using two specific tools, the KAT II inhibitor BFF 122 and the KMO inhibitor UPF 648.

Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG).

Altered EphA5 mRNA expression in rat brain with a single methamphetamine treatment.

Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity.

Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice.

This study examined the effects of the selective 5-HT1A receptor agonist osemozotan on repeated methamphetamine (METH)-induced behavioral sensitization and single METH-induced locomotor stimulant effect in mice, and then the neurochemical mechanisms using in vivo microdialysis. Repeated administration of METH for 7 days enhanced METH challenge-induced locomotor activity, and this sensitization was observed even after its withdrawal for 7-14 days. Administration of osemozotan to METH-sensitized mice inhibited the maintenance of behavioral sensitization.

Differential regulation by stimulants of neocortical expression of mrt1, arc, and homer1a mRNA in the rats treated with repeated methamphetamine.

The present work was conducted to obtain clues for the possible roles of a novel stimulant-inducible gene mrt1 (methamphetamine-responsive transcript 1) encoding a PDZ-PX protein in stimulant-induced behavioral sensitization. In the young adult rats, repeated daily treatment with methamphetamine (4 mg/kg, intraperitoneally, once a day) for 5 days caused an enhanced behavioral response to methamphetamine: behavioral sensitization. The 5-day intermittent administration of MAP upregulated the basal expression of mrt1 transcripts and eliminated the increasing effects of a challenge dose of MAP (1.