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Medication is a key treatment for patients with schizophrenia. Patients with schizophrenia tend to easily decrease medication adherence with long-term treatment. However, there is a chronic shortage of specialists who provide medication support, such as visiting nurses. In addition, these patients do not often use smartphones or PCs in their daily lives. Thus, schizophrenic patients need a direct approach in the physical world because they are unfamiliar with cyberspace. This study aims to improve the home treatment environment using robot technology that can approach in the physical world of schizophrenic patients who need medication support. In this study, collaboration between psychiatric nursing specialists and medical engineers investigated the interaction between communication robots and patients. The results showed that the robot was accepted by patients with schizophrenia as a talking partner. The amount of robot talking seemed to affect the impression of the robot on schizophrenics. Utterance process analysis showed that the smoothness of the conversation affected the relationship between robots and schizophrenics.

Tuberous sclerosis complex (TSC) is caused by mutations inTsc1orTsc2, whose gene products inhibit the small G-protein Rheb1. Rheb1 activates mTORC1, which may cause refractory epilepsy, intellectual disability, and autism. The mTORC1 inhibitors have been used for TSC patients with intractable epilepsy. However, its effectiveness for cognitive symptoms remains unclear. We found a new signaling pathway for synapse formation through Rheb1 activation, but not mTORC1. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib increased unfarnesylated (inactive) Rheb1 levels and restored synaptic abnormalities in culturedTsc2+/−neurons, whereas rapamycin did not enhance spine synapse formation. Lonafarnib treatment also restored the plasticity-related Arc (activity-regulated cytoskeleton-associated protein) expression in culturedTsc2+/−neurons. Lonafarnib action was partly dependent on the Rheb1 reduction with syntenin. Oral administration of lonafarnib increased unfarnesylated protein levels without affecting mTORC1 and MAP (mitogen-activated protein (MAP)) kinase signaling, and restored dendritic spine morphology in the hippocampi of maleTsc2+/−mice. In addition, lonafarnib treatment ameliorated contextual memory impairments and restored memory-related Arc expression in maleTsc2+/−micein vivo. HeterozygousRheb1knockout in maleTsc2+/−mice reproduced the results observed with pharmacological treatment. These results suggest that the Rheb1 activation may be responsible for synaptic abnormalities and memory impairments inTsc2+/−mice, and its inhibition by lonafarnib could provide insight into potential treatment options for TSC-associated neuropsychiatric disorders.SIGNIFICANCE STATEMENTTuberous sclerosis complex (TSC) is an autosomal-dominant disease that causes neuropsychiatric symptoms, including intractable epilepsy, intellectual disability (ID) and autism. No pharmacological treatment for ID has been reported so far. To develop a pharmacological treatment for ID, we investigated the mechanism of TSC and found that Rheb1 activation is responsible for synaptic abnormalities in TSC neurons. To inhibit Rheb1 function, we used the farnesyltransferase inhibitor lonafarnib, because farnesylation of Rheb1 is required for its activation. Lonafarnib treatment increased inactive Rheb1 and recovered proper synapse formation and plasticity-related Arc (activity-regulated cytoskeleton-associated protein) expression in TSC neurons. Furthermore,in vivolonafarnib treatment restored contextual memory and Arc induction in TSC mice. Together, Rheb1 inhibition by lonafarnib could provide insight into potential treatments for TSC-associated ID.

Background Medication is an important approach of treatment for patients with schizophrenia; however, the availability of visiting nurses and other human-related support is limited. This study aims to build a system in which service robots support the treatment of individuals with schizophrenia with medication at home. Moreover, medical staff can seamlessly monitor the status of their patients through the robots using this system. In this study, to develop a support system, interactions between a communication robot and patients were surveyed, with a focus on the patients’ impression of the robot and actual utterance times. Methods Communication between a commercially available communication robot and schizophrenic patients was investigated, particularly the participants’ feelings about the robot. In addition, the utterance data between the participants and the robot were extracted and the durations of the conversations were assessed. Results The examined interaction mode of a robot (talkative or not talkative) and whether the participant spoke or not (spoke or did not speak) revealed no significant association in all adjectives. A co-occurrence network graph showed differences in the participants’ impressions of the robot depending on how talkative the robot was. That is, when the robot did not initiate conversation often, the patient was more likely to initiate interactions and use longer phrases than when the robot initiated conversation frequently. Conversations also lasted longer when the participant, not the robot, initiated conversation. Conclusions People with schizophrenia converse with a robot regardless of whether the robot is talkative or not. Since the content of the conversation was not analyzed qualitatively, it is necessary to carefully examine whether people with schizophrenia can develop partnerships with robots.

The neural network undergoes remodeling in response to neural activity and interventions, such as antidepressants. Cell adhesion molecules that link pre- and post-synaptic membranes are responsible not only for the establishment of the neural circuitry, but also for the modulation of the strength of each synaptic connection. Among the various classes of synaptic cell adhesion molecules, a non-clustered protocadherin, Arcadlin/Paraxial protocadherin/Protocadherin-8 (Acad), is unique in that it is induced quickly in response to neural activity. Although the primary structure of Arcadlin implies its cell adhesion activity, it weakens the adhesion of N-cadherin. Furthermore, Arcadlin reduces the dendritic spine density in cultured hippocampal neurons. In order to gain an insight into the function of Arcadlin in the brain, we examined the dendritic morphologies of the hippocampal neurons in Acad−/− mice. Acad−/− mice showed a higher spine density than wild-type mice. Following an electroconvulsive seizure (ECS), which strongly induces Arcadlin in the hippocampus, the spine density gradually decreased for 8 h. ECS did not reduce the spine density of CA1 apical dendrites in Acad−/− mice. Daily intraperitoneal injection of the antidepressant fluoxetine (25 mg/kg/day) for 18 days resulted in the induction of Arcadlin in the hippocampus. This treatment reduced spine density in the dentate gyrus and CA1. Chronic fluoxetine treatment did not suppress spine density in Acad−/− mice, suggesting that fluoxetine-induced decrease in spine density is largely due to Arcadlin. The present findings confirm the spine-repulsing activity of Arcadlin and its involvement in the remodeling of hippocampal neurons in response to antidepressants.

本研究では、大学生のストレス反応の違いが認知的評価に及ぼす影響について検討した。大学生250 名 (男性：180 名、女性：70 名、平均年齢：19.8±1.6 歳) に対して質問紙調査 (ストレス反応尺度、認知的評価尺度) を実施した。その結果、対人・コントロール可能な状況 (状況2) および対物・コントロール不可能な状況 (状況3) では、ストレス低群の方がストレス高群よりも「コントロール可能性」得点が有意に高かった。対物・コントロール可能な状況 (状況4) では、ストレス低群の方がストレス高群よりも「コントロール可能性」得点が有意に高く、ストレス高群と比較して「脅威性」得点と「影響性」得点はストレス低群が有意に低かった。挑戦・脅威の状況 (状況5) では、ストレス低群の方がストレス高群よりも「挑戦」得点が有意に高かった。一方、「脅威性」得点はストレス高群が有意に高かった。これらの結果から、解決しやすい状況下では、ストレス高群の認知的評価はネガティブになりやすいことが示唆された。, This study examined the influence of differences in stress responses on cognitive appraisal in university students. Aquestionnaire survey (including the Stress Responses Scale and Cognitive Appraisal Scale) was administered to 250 university students(180 male, 70 female; average age: 19.8 ± 1.6 years). The results indicated that when the students were in a situation where they wereable to control other people (Situation 2 ) or were unable to control events (Situation 3), the scores for “Controllability” weresignificantly higher for students in the low-stress group than for those in the high-stress group. When the students were in a situationwhere they were able to control events (Situation 4), the scores for “Controllability” were significantly higher and the scores for “Threat”and “Effect” were significantly lower for students in the low-stress group. When the students were in a challenging and threateningsituation (Situation 5), the scores for “Challenge” were significantly higher and the scores for “Threat” were significantly lower forstudents in the low-stress group. The results indicate that the high-stress group tended to show negative cognitive appraisal under easilyresolvable situations.

Syntenin is an adaptor-like molecule that has two adjacent tandem postsynaptic density protein 95/Discs large protein/Zonula occludens 1 (PDZ) domains. The PDZ domains of syntenin recognize multiple peptide motifs with low to moderate affinity. Many reports have indicated interactions between syntenin and a plethora of proteins. Through interactions with various proteins, syntenin regulates the architecture of the cell membrane. As a result, increases in syntenin levels induce the metastasis of tumor cells, protrusion along the neurite in neuronal cells, and exosome biogenesis in various cell types. Here, we review the updated data that support various roles for syntenin in the regulation of neuronal synapses, tumor cell invasion, and exosome control.

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.

Recurrent seizures may cause neuronal damage in the hippocampus. As neurons form intimate interactions with astrocytes via glutamate, this neuron–glia circuit may play a pivotal role in neuronal excitotoxicity following such seizures. On the other hand, astrocytes contact vascular endothelia with their endfeet. Recently, we found kainic acid (KA) administration induced microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin E 2 (PGE 2 ) receptor EP3 in venous endothelia and on astrocytes, respectively. In addition, mice deficient in mPGES-1 exhibited an improvement in KA-induced neuronal loss, suggesting that endothelial PGE 2 might modulate neuronal damage via astrocytes. In this study, we therefore investigated whether the functional associations between endothelia and astrocytes via endothelial mPGES-1 lead to neuronal injury using primary cultures of hippocampal slices. We first confirmed the delayed induction of endothelial mPGES-1 in the wild-type (WT) slices after KA-treatment. Next, we examined the effects of endothelial mPGES-1 on Ca 2+ levels in astrocytes, subsequent glutamate release and neuronal injury using cultured slices prepared from WT and mPGES-1 knockout mice. Moreover, we investigated which EP receptor on astrocytes was activated by PGE 2 . We found that endothelial mPGES-1 produced PGE 2 that enhanced astrocytic Ca 2+ levels via EP3 receptors and increased Ca 2+ -dependent glutamate release, aggravating neuronal injury. This novel endothelium–astrocyte–neuron signaling pathway may be crucial for neuronal damage after repetitive seizures, and hence could be a new target for drug development.

Prostaglandin E2 (PGE2) is increased in the brain after kainic acid (KA) treatment. We previously demonstrated that KA also induces PG synthase cyclooxygenase-2 (COX-2) expression rapidly in neurons of the brain and slowly in astrocytes and endothelia. Prevention of KA-induced neuronal damage by nonneuronal COX-2 inhibition suggests a novel modulatory mechanism for neuronal injury by nonneuronal PGs. It remains unclear, however, which PG synthase is responsible for this modulation following COX-2 synthesis after neuronal insult. In addition, the PG receptor subtype that is involved in neuronal loss remains controversial. Here we demonstrate that microinjection of KA induces microsomal prostaglandin E synthase-1 (mPGES-1) in venous endothelial cells but not in neurons or astrocytes. We found that mPGES-1 plays a central role in delayed production of PGE2 and that mPGES-1-deficient mice exhibit significantly less neuronal loss induced by KA. Furthermore, KA injection caused an increase in the immunoreactivity for the EP3 receptor in the astrocytic endfeet that surround vascular endothelia. Neurons form intimate interactions with astrocytes via glutamate, and astrocytes contact vascular endothelia through endfeet. These findings suggest that endothelial cells may control neuronal excitotoxicity, most likely by regulating astrocytes via inducible PGE2. © 2009 Wiley-Liss, Inc.

本研究では、大学生のインターネット・携帯電話の利用状況と友人関係との関連について検討した。大学生270名に対して質問紙調査(インターネット・携帯電話の利用状況，学生用ソーシャルサポート尺度)を実施し、233名(回収率：86.3%)の回答が得られた。その結果、大学生においてはネット上で他者と交流をしている実態はあるが、それに傾倒していることはなく、日常の友人との交流も活発であった。そして、それぞれの友人には相応のサポートを期待し、上手く活用していると考えられた。, Investigation was made of the relationship between Internet and mobile phone usage and friendship among university students. Two surveys questionnaire (i.e., "Internet and Mobile Phone Usage" and "Social Support Scale for University Students") were administered to 270 university students (response rate: 86.3%). It was determined that although university students exchange ideas with each other over the Internet, students do not devote themselves intellectually to the interaction. It was observed that respondents had considerable daily interaction with friends. It was also noticed that university students expected support of some kind when communicating with friends, and students made good use of whatever support they received.

Synaptic activity induces changes in the number of dendritic spines. Here, we report a pathway of regulated endocytosis triggered by arcadlin, a protocadherin induced by electroconvulsive and other excitatory stimuli in hippocampal neurons. The homophilic binding of extracellular arcadlin domains activates TAO2beta, a splice variant of the thousand and one amino acid protein kinase 2, cloned here by virtue of its binding to the arcadlin intracellular domain. TAO2beta is a MAPKKK that activates the MEK3 MAPKK, which phosphorylates the p38 MAPK. Activation of p38 feeds-back on TAO2beta, phosphorylating a key serine required for triggering endocytosis of N-cadherin at the synapse. Arcadlin knockout increases the number of dendritic spines, and the phenotype is rescued by siRNA knockdown of N-cadherin. This pathway of regulated endocytosis of N-cadherin via protocadherin/TAO2beta/MEK3/p38 provides a molecular mechanism for transducing neuronal activity into changes in synaptic morphologies.

Injection of kainic acid (KA) into the brain causes severe seizures with hippocampal neuron loss. KA has been shown to immediately induce cyclooxygenase-2 (COX-2) expression in hippocampal neurons, indicating that neuronal COX-2 might be involved in neuronal death. In this study, however, we reveal that the delayed COX-2 induction in non-neuronal cells after KA injection plays an important role in hippocampal neuron loss rather than early COX-2 expression in neurons. We find that KA microinjection into the hemilateral hippocampus shows a later induction of COX-2 expression in non-neuronal cells, such as endothelial cells and astrocytes. In the KA-injected side, PGE2 concentration gradually increases and peaks at 24 h after injection, when non-neuronal COX-2 expression also peaks. When this delayed PGE2 elevation is prevented by selective COX-2 inhibitor NS398, it can block hippocampal cell death. Moreover, COX-2 knockout mice are also resistant to neuronal death after KA treatment. These findings indicate that delayed PGE2 production by non-neuronal COX-2 may facilitate neuronal death after seizure. Inhibition of COX-2 to an extent similar to PGE2 elevation after onset of seizure may be useful to prevent neuronal death.

本研究は、マウス腹腔マクロファージおよび脾細胞のサイトカイン産生能に及ぼす自由運動の影響について検討した。BALB/c系、雌マウス(12週齢)を運動群と対照群に区分し実験を行った。運動は、回転ケージを用いた自由運動を週3日、8週間実施した。腹腔マクロファージ機能において、リポ多糖刺激に対する一酸化窒素産生能およびインターロイキン(IL)-1β産生能は、対照群と比較して運動群が高い値を示し有意差が認められた。脾細胞機能において、concanavalin A (Con A) 刺激に対する脾細胞増殖反応は、運動群が有意に高い値を示した。Con A刺激に対する脾細胞のサイトカイン産生能では、運動群のIL-2およびインターフェロン-γが対照群より有意に高い値を示したが、IL-4産生能ではみられなかった。以上の結果から、8週間の自由運動は若齢マウスの腹腔マクロファージ機能および脾細胞の機能を向上させ、免疫機能増強作用のあることが示唆された。, This study was designed to evaluate the effects of voluntary running exercise on cytokine production of macrophage and lymphocyte. Twelve weeks old female BALB/c inbred mice were divided into two groups: a group has given voluntary running exercise (exercise group) and a non-exercise group (control group). Exercise consisted of spontaneous running in wheels 3 days per week for 8 weeks. The levels of nitric oxide and interleukin (IL)-1β production by lipopolysaccharide-stimulated peritoneal macrophages from the exercise group were significantly higher than those in the control group. Concanavalin A (Con A)-induced cell proliferation of the spleen in the exercise group was significantly higher than that in the control group. IL-2 and interferon-γ productions stimulated by Con A in the exercise group were significantly increased compared with the control group, but not IL-4 production. These results might suggest that 8-week voluntary running exercise effectively enhanced macrophage and lymphocyte functions in mice.

Endophilin 1 (Endo1) participates in synaptic vesicle biogenesis through interactions of its Src homology 3 domain with the polyphosphoinositide phosphatase Synaptojanin and the GTPase Dynamin. Endo1 has also been reported to affect endocytosis by converting membrane curvature via its lysophosphatidic acid acyltransferase activity. Here we report that a closely related isoform of Endo1, Endo3, inhibits clathrin-mediated endocytosis. Mutational analyses showed that the variable region of Endo3 is important in regulating transferrin endocytosis. In the brain, Endo3 is co-localized with dopamine D2 receptor in olfactory nerve terminals and inhibits its clathrin-mediated endocytosis in COS-7 cells. Furthermore, overexpression of Endo3 in an olfactory epithelium-derived cell line suppressed dopamine D2 receptor-mediated endocytosis and therefore accelerated its dopamine-induced differentiation. These results indicate that Endo3 may act as a negative regulator of clathrin-mediated endocytosis in brain neurons.

In this study, we determined the effects of recreational activities (recreation games) on profile of mood states (POMS) in a small group of general population (4 males and 18 females, 40.0±2.5 years of age). In the pre-recreational activities, the vigor score of the participant was the highest value (14.3±0.9), and the score of the other five factors ranges from 6.5 to 10.8 points. The vigor score in the post-activities was significantly (P

We investigated the relationship between Arc (activity-regulated cytoskeleton-associated protein) and Ca 2+ /calmodulin-dependent protein kinase II (CaM kinase II). Arc and CaM kinase II were concentrated in the postsynaptic density. These proteins were accumulated after electroconvulsive treatment. Arc increased about 2.5-fold within 30 min and was maintained at this level for 8 h after the stimulation. CaM kinase II also increased within 30 min and remained at this level for at least 24 h. The interaction of Arc with CaM kinase II was demonstrated using GST-Arc fusion protein, and confirmed in neuroblastoma cells by immunoprecipitation. We examined the function of Arc by introducing Arc cDNA into neuroblastoma cells expressing CaM kinase II. The cells expressing both Arc and CaM kinase II had longer neurites than those expressing CaM kinase II alone. Arc itself did not promote neurite outgrowth. The growth of neurites by Arc was completely blocked by treatment with KN62, an inhibitor of CaM kinases. These results indicated that Arc potentiated the action of CaM kinase II for neurite extension.

Brain cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, is rapidly and transiently induced by convulsions in hippocampal and cortical neurons. Therefore, we examined the effects of COX-2 on the 'rapid kindling' development in COX-2 knockout mice and in mice treated with nimesulide, a COX-2-selective inhibitor. Rapid kindling development was examined based on the incidence of hippocampal EEG seizures and behavioral seizures following repetitive electrical stimulation of the perforant path at an interval of 40 s, and on the total afterdischarge (AD) duration induced by 50 stimulations. In addition, we measured COX-2 mRNA expression by in situ hybridization and PGE2 concentration using enzyme immunoassay following rapid kindling stimulation. The results suggested that brain COX-2 mRNA levels were markedly increased in the hippocampal neurons and the concentration of PGE2 was elevated significantly, and that the incidence of AD and seizure behavior induction and the total AD duration were significantly decreased under conditions of COX-2 deficiency. Therefore, we concluded that inducible COX-2 facilitates the recurrence of hippocampal seizures.

The activity-regulated cytoskeleton-associated protein (Arc), encoded by the immediate early gene arc, is enriched in the brain and is hypothesized to play a role in the activity-dependent neuronal plasticity in the hippocampus. In the present study, the time course of Arc expression during the post-mating period was determined immunocytochemically, and the localization of Arc in the neurons in the accessory olfactory bulb (AOB) of female mice after mating was analyzed using immunocytochemical electron microscopy. Transient increases in the number of Arc-immunoreactive cells were observed in the glomerular, mitral/tufted cell and granule cell layers of the AOB after mating. In particular, the increase in the granule cell layer was remarkable, and larger than the increases in the other layers. In addition, electron microscopic observation revealed that Arc immunoreactivity was in the dendrites of the granule cells 1.5 h after mating. These results indicate that expression of Arc protein is induced rapidly and transiently in granule cell dendrites after mating. It is postulated that Arc protein has a role in the neuronal plasticity of the AOB after mating.

The expression of activity-related cytoskeleton-associated protein, Arc, could be useful as a marker for neuronal activity. We investigated Arc-immunoreactivity in both the accessory olfactory bulb (AOB) and the main olfactory bulb (MOB) of adult male rats in response to mating or exposure to female pheromones. Mating behavior strongly enhanced the Arc-immunoreactivity in the granule cell layer of the AOB. However, the enhancement of Arc-immunoreactivity by mating behavior was not observed in the MOB. These results showed that Arc-immunoreactivity was enhanced when the AOB received both afferent and efferent information during mating behavior. Hence, the expression of Arc in the AOB directly associates the pheromonal information with mating behavior. The AOB will provide a useful model to investigate the function of Arc protein.

Recent studies of the accessory olfactory bulb have shown that the expression of immediate-early genes, e.g., c-fos, c-jun and egr-1, can be used as a marker of neuronal activity in response to pheromonal cues. In this study, we analyzed the expression pattern, in response to mating, of the novel immediate-early gene product Arc (an activity-regulated cytoskeleton-associated protein). Arc is hypothesized to play a role in activity-dependent neuronal plasticity in the hippocampus. In a control group of male rats, only a small number of Arc-immunoreactive cells were observed in the accessory olfactory bulb. In a mating group, however, a marked increase in the number of Arc-immunoreactive cells was observed only in the granule cell layer of the accessory olfactory bulb. The increase in the number of Arc-immunoreactive cells after mating was similar to that observed for other immediate-early genes. However, for the mating group, the increase in Arc-positive cells was limited to the granule cell layer. Granule cells have been shown to exhibit a strong synaptic plasticity in response to pheromonal stimulation. From these findings we suggest that Arc plays an important role in neuronal plasticity in the accessory olfactory bulb.

Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulin-dependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

Mutations in the Tsc1 or Tsc2 genes cause tuberous sclerosis complex (TSC). Tsc1 and Tsc2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) signalling through Rheb-GTPase. We found that Tsc2(+/-) neurons showed impaired spine synapse formation, which was resistant to an mTORC1 inhibitor. Knockdown of mTOR also failed to restore these abnormalities, suggesting mTORC may not participate in impaired spinogenesis in Tsc2(+/-) neurons. To address whether Rheb activation impairs spine synapse formation, we expressed active and inactive forms of Rheb in WT and Tsc2(+/-) neurons, respectively. Expression of active Rheb abolished dendritic spine formation in WT neurons, whereas inactive Rheb restored spine synapse formation in Tsc2(+/-) neurons. Moreover, inactivation of Rheb with farnesyl transferase inhibitors recovered spine synapse morphogenesis in Tsc2(+/-) neurons. In conclusion, dendritic spine abnormalities in TSC neurons may be caused through activation of Rheb, but not through of mTORC1.

Epilepsy is one of the most common chronic brain disorders worldwide, affecting 1% of people across different ages and backgrounds. Epilepsy is defined as the sporadic occurrence of spontaneous recurrent seizures. Accumulating preclinical and clinical evidence suggest that there is a positive feedback cycle between epileptogenesis and brain inflammation. Epileptic seizures increase key inflammatory mediators, which in turn cause secondary damage to the brain and increase the likelihood of recurrent seizures. Cytokines and prostaglandins are well-known inflammatory mediators in the brain, and their biosynthesis is enhanced following seizures. Such inflammatory mediators could be therapeutic targets for the development of new antiepileptic drugs. In this review, we discuss the roles of inflammatory mediators in epileptogenesis.

We studied the effects of voluntary exercise on nonspecific immunological mechanisms in mice. In this study, 7 week old male ICR mice were divided into two groups: a non-exercise group (control) and a group given voluntary exercise (Vex group). Each mouse of the Vex group was kept in an individual cage equipped with a voluntarily revolving wheel that the mouse had free access to. The duration of voluntary exercise was 3 days per week for 8 weeks. The following results were obtained: 1) After 8 weeks of voluntary exercise, food consumption, the weight of the anterior tibialis muscle and succinate dehydrogenase activity in the anterior tibialis muscle increased significantly in the Vex group compared to the control group. 2) By means of the carbon clearance method, phagocytosis of the reticuloendothelial system was increased in the Vex group. 3) Glucose consumption capacity and O-2 production capacity of peritoneal macrophages (M phi) were significantly increased in the Vex group compared to the control group. 4) The acid phosphatase (APH), beta-glucuronidase (GLU) and lactate dehydrogenase (LDH) activities of peritoneal M phi increased significantly in the Vex group. 5) Concanavalin A (Con A)-induced cell proliferation in the spleen was high in the Vex group. Based on the above findings, it may be surmised that voluntary exercise enhances nonspecific immunological mechanisms and thereby improves the host defense mechanisms in mice.

Necdin is a 325 amino acid residue protein encoded by a cDNA clone isolated from neurally differentiated embryonal carcinoma cells. In situ hybridization histochemistry revealed that necdin mRNA-containing cells in vivo coincided with postmitotic neurons in the mouse brain from early periods of neurogenesis until adulthood. To study the regulation of necdin gene expression, we have isolated and characterized the necdin gene from a mouse genomic DNA library. The necdin gene contains no intron, and its upstream region lacks canonical TATA and CAAT boxes. To assess promoter activity, the 5′-flanking sequence (844 base pairs) of the necdin gene was fused to the LacZ reporter gene and transiently transfected into retinoic acid-treated P19 embryonal carcinoma cells. Most of the transfectants expressing high levels of LacZ immunoreactivity were postmitotic neurons differentiated from P19 cells. Deletion analysis using luciferase reporter genes demonstrated that a neuron-restrictive core promoter is localized to positions −80 to −35, in which a G+C-rich domain and a putative binding site for transcription factors with PAS (per, arnt, and single-minded) dimerization domain are comprised. These results suggest that postmitotic neuron-restrictive expression of the necdin gene is mediated by the specific cis-acting elements and that this promoter is applicable to postmitotic neuron-targeted expression of various transgenic systems.