Akihiro Mouri

うつ病の病態にはモノアミン仮説が提唱されており,抗うつ薬の主流が選択的セロトニン(5-HT)再取り込み阻害薬であることから,特に5-HT神経系の機能低下が広く受け入れられている.しかし,患者の約1/3は既存の抗うつ薬に対して難治性であるため,新しい創薬ターゲットに対する新規抗うつ薬の開発が求められている.トリプトファン(TRP)は5-HT経路だけでなくキヌレニン(KYN)経路においても代謝される.インドールアミン2,3-ジオキシゲナーゼ1(IDO1)は,TRP-KYN経路の代謝を行う最初の律速酵素である.IDO1は炎症性サイトカインによって強く誘導され,TRPを代謝し,5-HT経路で代謝されるTRPレベルを低下させ,その結果,5-HT合成を抑制し,うつ様行動を惹起する.下流のキヌレニン-3-モノオキシゲナーゼ(KMO)は,KYNを3-ヒドロキシキヌレニンに代謝する重要な酵素である.KMOが欠損すると,キヌレニンアミノトランスフェラーゼ(KAT)によりKYNが代謝され,キヌレン酸(KA)が増加し,うつ様行動が惹起される.一方,慢性予測不能軽度ストレス(CUMS)は視床下部-下垂体-副腎皮質(HPA)系を破綻させ,前頭前野におけるKMOの発現が低下し,KAを増加させる.これにはCUMSによるKMOを主に発現するミクログリアの減少を伴っている.KAはα7ニコチン性アセチルコリン受容体(α7nAChR)アンタゴニスト作用を有する.ニコチンやガランタミンによるα7nAChRの活性化により,CUMS誘発のうつ病様行動が減弱される.IDO1の誘導による5-HT合成抑制と,KMO発現低下を介したKAレベルの増加によるα7nAChR拮抗作用はうつ様行動を引き起こすことから,TRP-KYN経路の代謝的変化がうつ病の病態に深く関与していると考えられる.TRP-KYN経路は,うつ病の新規診断方法や抗うつ薬の開発に向けた魅力的なターゲットになることが期待される.(著者抄録)

Introduction: Burning mouth syndrome and atypical odontalgia (BMS/AO) are chronic orofacial pain conditions in the absence of any identifiable odontogenic pathology. The pain is treatment-resistant and frequently causes depressive symptoms. Duloxetine (DLX), a serotonin-noradrenaline reuptake inhibitor, is not only used as therapy for depression, but also for chronic orofacial pain. Since their mechanisms in detail remains unknown, in this study, we focused on serotonin transporter (SERT), one of DLX action site, and investigated association between expression of SERT and effect of DLX on pain in BMS/AO. Methods: The patients with BMS/AO, were assessed for severity of pain using the visual analog scale (VAS) and for signs of depression using the Hamilton Depression Rating Scale (HDRS). In their platelets before (baseline) and 12 weeks after DLX-treatment, the expression of total and ubiquitinated SERT proteins was confirmed by Western blot. This study was approved by the Ethics Review Committees of Nagoya, Aichi Gakuin, and Meijo Universities. Results: The expression of total and ubiquitinated SERT protein at baseline in all patients were higher and lower, respectively, compared to those in controls. After the DLX-treatment, there was no difference in the total SERT protein levels between the patients and controls. The mean of VAS and HDRS scores or the expression of total SERT protein were significantly decreased after the treatment, compared to those at baseline.  Conclusions: These results indicate that DLX relieves chronic orofacial pain in patients with BMS/AO, and such effect may be mediated via SERT downregulation.

Exposure to psychosocial stress (e.g., bullying) in juveniles is a risk factor of stress-related psychiatric disorders later in life. The exposure to stress activates microglia, which plays an important role in brain immunity, and induces neuroinflammation. It is unclear to what degree the exposure to psychosocial stress as juveniles is affected to brain immunity systems and neuronal morphology. The present study was examined expression of inflammatory cytokines or inflammatory signal-related molecules and neuronal morphology in the prefrontal cortex (PFC) by using the mice exposed to social defeat stress as juveniles. We found that inflammation or immune system-related genes of defeated mice were significantly changed, compared to those of non-defeated mice in transcriptome analysis. Especially, the high expressions of Ca2+ binding protein, S100A8, and S100A9 genes were observed in the PFC of defeated mice. The levels of TNF-α and the numbers of spines in defeated mice were significantly increased and decreased, respectively, compared to that in non-defeated mice. There were no significant changes of TNFR1, NF-κB, or I-κB levels in defeated mice. Administration of R-7050, a TNF-α receptor antagonist, didn't develop the impairment of social behaviors induced by social defeat stress exposure as juveniles. Our findings suggest that exposure to social defeat stress as juveniles induces TNF-α mediated neuroinflammation via the activated microglia.

Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of autism spectrum disorder (ASD) in the offspring. In the pathophysiological hypothesis of ASD, excitation/inhibition (E/I) imbalance is attracted. Dysfunction of serotonergic system is also suggested to be involved in ASD. In this study, we investigated glutamatergic-serotonergic neuronal interaction in the ASD-like behavior induced by prenatal VPA exposure in mice. Prenatal VPA exposure induced not only excessive repetitive self-grooming behavior, impairments of social behavior and object recognition memory, but also increased glutamatergic signaling (CaMKII phosphorylation) and decreased serotonin contents in the prefrontal cortex. Memantine (low-affinity NMDA antagonist) suppressed both the increase of CaMKII phosphorylation and ASD-like behaviors. Activation of serotonergic signaling via 5-HT_1A receptor by fluoxetine, tandospirone (5-HT_1A receptor agonist) and optogenetics attenuated the ASD-like behaviors in prenatal VPA-exposed mice. WAY-100635 (5-HT_1A receptor antagonist) antagonized the effect of fluoxetine on the ASD-like behaviors. These results suggest that the hyper-NMDA receptor signaling and ASD-like behaviors are associated with hypo-signaling of 5-HT_1A receptor in the prenatal VPA-exposed mice.

Chronic stress contributes to the pathogenesis of major depressive disorder (MDD). In the kynurenine pathway (KP), kynurenine is metabolized to 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO) and to kynurenic acid (KA) by kynurenine aminotransferase. KP alternation has been reported to be associated with the pathogenesis of MDD. We investigated the involvement of KP in the depressive-like behavior induced by chronic unpredictable mild stress (CUMS). Mice were randomly exposed to 9 kinds of mild stressors for 4 weeks. Corticosterone level in the serum and corticotropin-releasing hormone (CRH) mRNA level in the hypothalamus (HT) elevated immediately after CUMS. Further, KMO mRNA level was decreased, but KA content was increased in the prefrontal cortex (PFC). Because KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, we investigated the effects of nicotine (Nic) and galantamine (Gal :α7nAChR agonist) on the depressive-like behavior and dysregulation of HPA axis induced by CUMS. When Nic and Gal were administrated before exposure to each stressor during CUMS, they attenuated CUMS-induced decreased sociability. Although Nic failed to inhibit elevated corticosterone level in the serum immediately after CUMS, but suppressed that sustained elevation 1 week after CUMS. Alternation of KP from 3-HK to KA through downregulation of KMO may be involved in the depressive-like behavior and the sustained elevation of serum corticosterone 1 week after CUMS.

Adolescent binge drinking represents a major public health challenge and lead to persistent psychiatric disorders. However, the underlying pathogenic mechanisms remain poorly understood. Myelin abnormalities were observed in human subjects with alcohol abuse. Gray matter myelination in the prefrontal cortex and hippocampus during adolescence are vulnerable to alcohol.In the present study, we investigated whether myelin abnormalities in the gray matter are involved in behavioral abnormalities induced by adolescent binge ethanol treatment (ABET). To produce ABET, C57BL/6J mouse was given EtOH (3.0g/kg, i.e. 25% ethanol w/v) once a day during adolescence (P28-46) in an intermittent fashion. ABET persistently developed behavioral abnormalities such as anxiety-like behaviors in the marble burying test and the novelty suppressed feeding test, impaired memory function in the novel object recognition test, and impairments of social behavior in social interaction test. ABET decreased myelin-related protein and oligodendrocyte lineage cells in the prefrontal cortex and hippocampus. Clemastine, which promotes oligodendroglial differentiation and myelination, rescues the behavioral abnormalities. These findings suggest that myelin abnormalities in the gray matter may be involved in the behavioral abnormalities caused by ABET in adulthood.

Dopamine contributes to attention as a key neurotransmitter in the nervous system projecting to the forebrain. Numerous animal models have been generated to model attentional impairment with dopaminergic dysregulation. We previously generated mice lacking Shati, an N-acetyltransferase-8-like protein, on a C57BL/6J genetic background (Shati/Nat8l^−/−). Modulation of this gene leads to changes in behavioral phenotypes such as attentional impairment associated with hypodopaminergic neurotransmission in mice. In this study, the effect of Shati/Nat8l deficit in dopaminergic projections was investigated using an object-based attention test (OBAT). Shati/Nat8l^−/− mice showed attentional impairment in the OBAT, accompanied by reduced neuronal activity in the prefrontal cortex (PFC) and the hypodopaminergic function indicated by the reduced expression of tyrosine hydroxylase (dopaminergic marker) protein and dopamine-related genes in the ventral tegmental area (VTA). The activation of dopaminergic projections of the VTA-PFC by chemogenetic stimulation ameliorated the attentional impairment in Shati/Nat8l^−/− mice. These results confirm previous findings that Shati/Nat8l deficiency interrupts the dopaminergic system and contributes to novel evidence that Shati/Nat8l is implicated in the dopaminergic projections of the VTA-PFC, which play important roles in the regulation of attention in the OBAT.

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). We will introduce the involvement of TRP metabolism in the depression-like behavior induced by chronic unpredictable mild stress (CUMS). Corticosterone level in the serum and corticosterone-releasing hormone (CRH) mRNA level in the hypothalamus (HT) were elevated immediately after CUMS. Associated with the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, KMO mRNA level was decreased, and KA content was increased in the prefrontal cortex (PFC). Microglia marker Iba-1 was decreased immediately after CUMS. Because KMO is mainly found in microglia in the central nervous system, these results suggests that CUMS increased KA contents via alternation of kynurenine metabolic enzyme from KMO to KATs due to the reduction of microglia. Because KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, we investigated the effect of nicotine and galantamine (allosteric potentiating ligand for α7nAChR ) on the depression-like behavior and dysregulation of HPA axis induced by CUMS. When nicotine and galantamine were administrated before exposure to each stressor, they attenuated CUMS-induced depression-like behaviors. Although nicotine didn't affect elevated corticosterone level in the serum immediately after CUMS, it suppressed the sustained elevation 1 week after CUMS. Increase of KA associative with downregulation of KMO in microglia was involved in the depressive-like behavior and the sustained elevation of serum corticosterone after CUMS. The ameliorating effects of nicotine and galantamine on depression-like behaviors induced by CUMS are associated with the activation of α7nAChR.

Major depressive disorder (MDD) is a common mental disorder characterized by reduced motivation, diminished interest and pleasure, and anhedonia. We have proposed melanoma-associated antigen D1 (MAGE-D1) knock out (KO) mouse is a MDD model, and which involves the serotonergic hypofunction. However, not only serotonergic but also noradrenergic neuronal malfunctions are involved in depressive behaviors. Here, we investigate the involvement of noradrenergic neuronal system in depression-like behaviors of MAGE-D1 KO mice. MAGE-D1 KO mice showed decreases in locomotor activity, social interaction time and sucrose preference, but increases in immobility time in the forced swimming test (FST), and feeding latency in the novelty suppression feeding test. Noradrenaline (NA) tissue contents in the prefrontal cortex, hippocampus, and amygdala, and potassium-evoked noradrenaline releases in the prefrontal cortex and hippocampus were decreased in MAGE-D1 KO mice. The protein expression of noradrenaline transporter (NAT) was increased in the prefrontal cortex of the MAGE-D1 KO mice. Phosphorylation of NAT at threonine and protein expression of its kinase, protein kinase C (PKC) were decreased, but not changed in ubiquitination or expression of NAT mRNA. Acute administration of NA reuptake inhibitors (desipramine and atomoxetine) attenuated increase in immobility time in the FST and decrease in sucrose preference, but not other behavior changes in MAGE-D1 KO mice. These results suggested that depression-like behaviors in MAGE-D1 KO mice might be associated with hypofunction of noradrenergic neuronal system due to NAT overexpression through decrease in PKC-dependent phosphorylation of NAT.

White matter abnormalities have been implicated in psychiatric diseases such as major depressive disorder (MDD) ; however, the underlying mechanisms remain poorly understood. The structure and function of the corpus callosum are particularly vulnerable to stress, which may lead to MDD. In the present study, we investigated whether chronic social defeat stress (CSDS) induces myelin abnormalities of the corpus callosum through inflammation that contributes to the pathogenesis of MDD. To produce CSDS, the adult C57BL/6J mouse was exposed to an aggressor ICR mouse for 10 consecutive days. CSDS decreased mature oligodendrocytes in the corpus callosum, and persistently developed depression-like behaviors such as increased immobility in the forced swimming test and impaired social interaction. On transmission electron microscopy, myelin abnormalities and axonal degeneration were observed with necrosis-like cell death of oligodendrocytes in the corpus callosum. Interestingly, CSDS significantly increased the Gasdermin D (Gsdmd), a marker of pyroptosis, concomitantly with enhanced IL-1β production in the corpus callosum. Administration of IL-1β inhibitor prevented the decrease of oligodendrocytes and CSDS-induced depression-like behaviors. These findings suggest that IL-1β acts as a crucial mediator of oligodendroglial pyroptosis induced by the CSDS, which may be responsible for the development of MDD.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficit and stereotyped, repetitive patterns of behaviors and interests. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in the offspring. In the pathophysiological hypothesis of ASD, excitation/inhibition (E/I) imbalance is attracted. In this study, we investigated how VPA (500 mg/kg) at embryonic day 12.5 changes the emotional, cognitive and glutamatergic functions in the offspring of mice. Prenatal VPA exposure induced excessive repetitive self-grooming behavior, impairments of social behavior and object recognition memory, increased glutamatergic signaling [i.e. phospho-Ca²+/calmodulin-dependent protein kinase II (CaMKⅡ)and phospho-protein kinase C (PKC) levels] and decreased serotonin contents in the prefrontal cortex. These results suggested that VPA-exposure induced ASD-like behaviors associated with hyper-excitation of glutamatergic and hypo-serotonergic functions in the prefrontal cortex. Activation of serotonergic system by fluoxetine (20mg/kg) attenuated the VPA-induced ASD-like behaviors and hyper-glutamatergic signaling in the prefrontal cortex. These results suggest that hypo-serotonergic function is involved in the prenatal VPA-induced ASD-like behaviors and hyper-excitation in the prefrontal cortex.

Major depressive disorder (MDD) is a worldwide serious psychiatric disease, and more than 300 million people suffer from MDD. Chronic stress contributes to the pathogenesis of MDD. Cigarette smoking is strongly associated with MDD. Epidemiological and clinical studies claim that the smoking is assumed as self-medication for stress and depression. In this study, we investigated the effect of nicotine on the depression-like behavior induced by chronic unpredictable mild stress (CUMS). At the age of 6 weeks, C57BL6J mice were randomly exposed to 9 kinds of mild stressors for 4 weeks. Nicotine (0.2mg/kg), galantamine (1mg/kg) and varenicline (1mg/kg) were administrated 30 min before exposure to each stressor during CUMS. After CUMS, mice were subjected social interaction test and measured serum corticosterone levels and mRNA levels of  nicotinic acetylcholine receptor (nAChR) subunits in the prefrontal cortex (PFC). Nicotine attenuated decrease in social interaction time of CUMS mice. Nicotine did not affect elevated serum corticosterone levels immediately after CUMS but reversed the sustained elevation after behavioral test. CUMS did not affect mRNA levels of α7, α4 or β2 nAChR subunit in the PFC. Finally, we evaluated the efficacies of galantamine, α7 nAChR allosteric modulator and varenicline, α4β2 nAChR partial agonist on CUMS mice. Administration of galantamine, but not varenicline attenuated decrease in social interaction time of CUMS mice. These data suggested that α7 nAChR is an important target for stress resilience and development of antidepressant.

Chronic stress contributes to the pathogenesis of major depressive disorder (MDD). The efficacy of ketamine on the treatment-resistant MDD implies the involvement of glutamatergic dysregulation in its pathophysiology. We recently demonstrated the abnormalities of ubiquitin-proteasome system (UPS) in the pathophysiology of MDD. In the present study, we investigated the involvement of glutamatergic dysregulation by UPS in chronic social defeat stress (CSDS)-induced depression-like behavior. To induce CSDS, the adult C57BL/6J mouse was exposed to aggressor ICR mouse for 10 consecutive days. CSDS reduced the duration of time spent at the interaction zone in the social interaction test. Increase in high potassium-induced release of glutamate was diminished in the prefrontal cortex (PFC) of the stressed mice. Interestingly, ubiquitinated but not total glutamate transporter 1 (GLT-1) was decreased in the PFC of the stressed mice. Protein levels of neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4L) and ubiquitin-conjugating enzyme E2D2 (Ube2d2) were also reduced in the stressed mice. Injection of adeno-associated virus (AAV) expressing shRNA against Nedd4L into the PFC exacerbated the social impairments induced by CSDS. These results suggest that CSDS induces depressive-like behavior and glutamatergic dysfunction, through the decrease of GLT-1 ubiquitination by down-regulation of Ube2d2-Nedd4L pathway. Taken together, GLT-1 ubiquitination could play crucial roles in the pathophysiology of MDD.

It has been shown that adverse events during pregnancy have a negative impact on brain development and may increase the risk for neuropsychiatric disorders in later life in human. In this study, we explored the long-lasting influences of psychosocial stress during pregnancy in adult offspring of mice using a communication box method.    Pregnant C57BL/6J mice were exposed to a psychosocial stress by communication box daily from the gestational day 12 (G12) until delivery. We observed the behaviors of offspring at 7 weeks old in the social interaction and elevated plus-maze tests, and measured plasma corticosterone levels, GABAergic neuronal changes in the amygdala. We found anxiety-like behaviors and reduction of social interaction in offspring received prenatal stress. Those mice had decrease in parvalbumin-positive cells in the amygdala and a hyperactivity of stress-induced corticosterone release compared to control group. In addition, these anxiety-like behaviors in the both tests were blocked by intra-amygdala injection of diazepam.  These results suggest that this prenatal psychosocial stress may lead to GABAergic hypofunction in the amygdala accompanied with anxiety-like behaviors of offspring.

Schizophrenia is a severe and common psychiatric disease characterized by hallucinations, delusions, deficit in motivation and cognitive dysfunction. Because many patients show poor or partial response to antipsychotic treatment, it is important to develop novel therapeutic interventions with greater efficacy through new mechanism of action. The hypothesis of inflammation‐induced neurodevelopmental impairment and glutamatergic hypofunction have been proposed as the etiology/pathophysiology of schizophrenia. Kynurenine metabolism is activated by inflammation and there are some metabolites which induce neurotoxicity and affect glutamatergic transmission. Based on the epidemiological hypothesis that maternal gestational exposure to human influenza virus induces vulnerability for the onset of the schizophrenia, embryos of mice are exposed the viral mimic polyriboinosinic‐polyribocytidilic acid (poly I : C) during prenatal period to develop the schizophrenia‐like animal model. In this review, we summarize schizophrenia‐like animal model with neurodevelopmental impairment induced by the prenatal poly I : C exposure and an involvement of kynurenine metabolism in the animal model induced by the prenatal poly I : C exposure. No potential conflicts of interest were disclosed.

Successful completion of daily activities relies on the ability to select the relevant features of the environment for memory and recall. Disruption to these processes can lead to various disorders, such as attention-deficit hyperactivity disorder (ADHD). Dopamine is a neurotransmitter implicated in the regulation of several processes, including attention. In addition to the higher-order brain function, dopamine is implicated in the regulation of adult neurogenesis. Previously, we generated mice lacking Shati, an N-acetyltransferase-8-like protein on a C57BL/6J genetic background (Shati/Nat8l-/- ). These mice showed a series of changes in the dopamine system and ADHD-like behavioral phenotypes. Therefore, we hypothesized that deficiency of Shati/Nat8l would affect neurogenesis and attentional behavior in mice. We found aberrant morphology of neurons and impaired neurogenesis in the dentate gyrus of Shati/Nat8l-/- mice. Additionally, research has suggested that impaired neurogenesis might be because of the reduction of dopamine in the hippocampus. Galantamine (GAL) attenuated the attentional impairment observed in the object-based attention test via increasing the dopamine release in the hippocampus of Shati/Nat8l-/- mice. The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, and dopamine D1 receptor antagonist, SCH23390, blocked the ameliorating effect of GAL on attentional impairment in Shati/Nat8l-/- mice. These results suggest that the ameliorating effect of GAL on Shati/Nat8l-/- attentional impairment is associated with activation of D1 receptors following increased dopamine release in the hippocampus via α7 nicotinic acetylcholine receptor. In summary, Shati/Nat8l is important in both morphogenesis and neurogenesis in the dentate gyrus and attention, possible via modulation of dopaminergic transmission.

We investigated the possibility of prostaglandin E₂ (PGE₂) as one of common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental factors. PGE₂ levels in whole brain were significantly increased after exposure to viral infection [injection of polyinosinic-polycytidylic acid (polyI:C)], hypoxia (exposure to CO₂), and neglect (separation from the dams) in postnatal day (PD) 2, compared to those after non-exposure. The mice administered polyI:C during PD 2-6 exhibited the impairment of sociality, object recognition memory, and pre-pulse inhibition (PPI) in adult at PD 70, and further, significant decreased spine density of the mPFC in adult mice. Exposure to CO₂ at PD 2 and separation from dams during PD 2-21 exhibited the impairment of PPI and decrease of spine density in adult mice. These behavioral impairments induced by administration of polyI:C were recovered by an inhibition of PGE₂-EP1 (PGE₂ receptor subtype) and of cyclooxygenase (COX).  Our findings suggest that PGE₂ is one of potential common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental factors, and PGE₂ plays a crucial role in the development of behavioral and neuronal impairments, which are associated with activation of PGE₂-EP1.

Quinolinic acid phosphoribosyltransferase (QPRT) metabolizes quinolinic acid (QA) to nicotinamide adenine nucleotide (NAD⁺) via kynurenine pathway. QA is a excitotoxic substance that activate N-methyl-D-aspertate (NMDA) receptors and NAD⁺ is essential for cell survival. In this study, we evaluated QPRT knock out (KO) mice to explore the physiological role of QPRT in central nervous system. QPRT KO mice demonstrated motor deficits (decrease of locomotor activity, decrease of duration time to maintain balance on the rotarod, wide stance in footprint pattern test) and cognitive deficits (decrease of spontaneous alternation behavior in Y-maze test, and prolongation of latency to enter the target hole in the Barnes-maze test). But emotional change was not observed except for decrease in number of buried marbles in marble burying test. Dopaminergic dysfunction was observed in prefrontal cortex, nucleus accumbens and striatum of QPRT KO mice. Dopamine D₁ receptor agonist (SKF81297)-induced hyperactivity is not observed in QPRT KO mice. Dopamine D₂ receptor antagonist (raclopride)-induced catalepsy is more sensitive in QPRT KO mice. The activation of dopaminergic function by methylphenidate attenuated the impairment of short-term memory and hypoactivity of QPRT KO mice. QPRT KO mice showed increased level of QA in serum but normal level of NAD+ in brain. QA-mediated NMDA receptor signaling (phosphorylation of CaMK2 and activation of calpain) and oxidative stress were enhanced in prefrontal cortex, nucleus accumbens and striatum of QPRT KO mice. These results suggested that deficiency of QPRT lead motor and cognitive deficits associated with dopaminergic dysfunction via QA-induced calpain activation and oxidative stress.