A hybrid approach for the analysis of complex categorical data structures: assessment of latent distance learning perception in higher education.

A long tradition of analysing ordinal response data deals with parametric models, which started with the seminal approach of cumulative models. When data are collected by means of Likert scale survey questions in which several scored items measure one or more latent traits, one of the sore topics is how to deal with the ordered categories. A stacked ensemble (or hybrid) model is introduced in the proposal to tackle the limitations of summing up the items. In particular, multiple items responses are synthesised into a single meta-item, defined via a joint data reduction approach; the meta-item is then modelled according to regression approaches for ordered polytomous variables accounting for potential scaling effects. Finally, a recursive partitioning method yielding trees provides automatic variable selection. The performance of the method is evaluated empirically by using a survey on Distance Learning perception.

The impact of cystic fibrosis on the working life of patients: A systematic review.

Advances in the treatment and management of cystic fibrosis (CF) have led to a substantial increase in patient life expectancy, thus facilitating healthier lives and labour force participation. This review aimed to address the impact of CF on the occupational functioning of patients. A significant proportion of patients were reported to retain a job on a full- or part-time schedule. Less physically demanding occupations were most frequently performed, perhaps due to CF-related inability to sustain a heavy workload. Disease severity parameters (e.g., lung function measurements, or personal, psycho-social, or economic conditions) have been reported as determinant or co-determinant factors for the development of work-related disability. Although further research is necessary, our results may be useful to inform interdisciplinary CF healthcare management, including the assessment of work function, and to define career counselling plans and workplace risk assessment and management strategies to support the personal, social and professional lives of patients.

Employment Status and Work Ability in Adults with Cystic Fibrosis.

Improvements in the survival and clinical outcomes of cystic fibrosis (CF) patients raised questions about their workforce participation and capacity to work. One hundred and ninety-six outpatients, attending the Adult CF Center of an Italian University Hospital, were enrolled between May 2020 and March 2021. The patients' personal and clinical characteristics, employment status, and profession were assessed. The Cystic Fibrosis Questionnaire-Revised and the work ability index (WAI) were employed to assess CF health-related quality of life and the employee's perception of their ability to work, respectively. Among the enrolled patients, 98 (50%) were employed. The non-working subjects were significantly younger (mean age ± standard deviation: 30 ± 10 vs. 37 ± 10 years) and were diagnosed with CF significantly earlier (9 ± 13 vs. 17 ± 18 years) than the employed subjects. The vast majority of CF workers (82.6%) were employed in tertiary professions. A general good work ability perception was determined in the employed population. Aging and being employed for >15 years could significantly predict a reduction in work ability, while a better quality of life was a positive predictor for its enhancement. Although further research is necessary, these results may introduce interdisciplinary CF healthcare management that includes a work function assessment, formal career counseling, and job guidance to support the personal, social and professional lives of CF patients.

The Impact of Shift-Work and Night Shift-Work on Thyroid: A Systematic Review.

Thyroid hormones are regulated by the pituitary thyroid stimulating hormone (TSH), whose secretion presents a circadian rhythmicity. Indeed, it is conceivable that shift- and night shift-work, affecting sleep-wake rhythms, may impact thyroid functionality. Therefore, the aim of the present review was to provide an overview on the association between shift- and night shift-work and thyroid hormonal changes and disease development. A systematic review of studies available in PubMed, Scopus, and ISI Web of Science databases was performed. A positive association between night shift-work and increased TSH concentrations was reported by most of the reviewed investigations. Inconclusive evidence was available on thyroid diseases. However, the limited number of studies, the noticeable heterogeneity in the shift-work scheduling, in terms of amount, duration, type of shift- or night shift-work, prevents easily integrating findings and extrapolating definite conclusions. Further investigation seems necessary to better define the relationship between shift schedules and different thyroid outcomes, and possible long-term implications of early functional changes. Overall, this may support the adoption of advanced risk assessment and management strategies aimed to achieve a safer workplace organization and a timely, responsible realization of all the benefits of a 24-h economy.

Characterization of the sensory, affective, cognitive, biochemical, and neuronal alterations in a modified chronic constriction injury model of neuropathic pain in mice.

The chronic constriction injury (CCI) of the sciatic nerve is a nerve injury-based model of neuropathic pain (NP). Comorbidities of NP such as depression, anxiety, and cognitive deficits are associated with a functional reorganization of the medial prefrontal cortex (mPFC). Here, we have employed an adapted model of CCI by placing one single loose ligature around the sciatic nerve in mice for investigating the alterations in sensory, motor, affective, and cognitive behavior and in electrophysiological and biochemical properties in the prelimbic division (PrL) of the mPFC. Our adapted model of CCI induced mechanical allodynia, motor, and cognitive impairments and anxiety- and depression-like behavior. In the PrL division of mPFC was observed an increase in GABA and a decrease in d-aspartate levels. Moreover an increase in the activity of neurons responding to mechanical stimulation with an excitation, mPFC (+), and a decrease in those responding with an inhibition, mPFC (-), was found. Altogether these findings demonstrate that a single ligature around the sciatic nerve was able to induce sensory, affective, cognitive, biochemical, and functional alterations already observed in other neuropathic pain models and it may be an appropriate and easily reproducible model for studying neuropathic pain mechanisms and treatments.

Opportunities and challenging issues of nanomaterials in otological fields: an occupational health perspective.

Nanotechnology may offer innovative solutions to overcome the physiological and anatomical barriers that make the diagnosis and treatment of ear diseases an extremely challenging issue. However, despite the solutions provided by nano-applications, the still little-known toxicological behavior of nanomaterials raised scientific concerns regarding their biosafety for treated patients and exposed workers. Therefore, this review provides an overview on recent developments and upcoming opportunities in nanoscale otological applications, and critically assesses possible adverse effects of nanosized compounds on ear structures and hearing functionality. Although such preliminary data do not allow to draw definite strategies for the evaluation of nanomaterial ototoxicity, they can still be useful to improve scientific community and workforce awareness regarding possible nanomaterial adverse effects on ear.

Reply to Accelerated Silicosis-An Emerging Epidemic Associated with Engineered Stone. Comment on Leso, V. et al. Artificial Stone-Associated Silicosis: A Systematic Review. Int. J. Environ. Res. Public Health 2019, 16(4), 568, doi:10.3390/ijerph16040568.

Our systematic review on artificial stone (AS)-associated silicosis and the related comment by Edwards underline the urgency to define effective strategies to assess and manage the risk of exposure to silica in workers involved in AS job tasks. Case screening programs may be important to fully understand the extent of the silicosis epidemic associated with AS and point out critical issues in workplace settings/practices that, by contributing to higher respirable crystalline exposure, favor the disease manifestation. This information may guide the identification of the most appropriate preventive measures in workplaces, especially regarding the administration of updated training and information courses, the definition of good working practices, and the application of targeted health surveillance programs. However, considering the recent epidemiological data and the severity of AS-associated silicosis, it would be appropriate (according to the hierarchy of control strategy) to also consider the application of more stringent prevention measures, such as a safety-by-design approach to the chemical formulation of the AS. Overall, the implementation of the aforementioned preventive measures should ensure an effective control of the current silicosis epidemic and, at the same time, prevent the development of new disease cases in the near future.

Artificial Stone Associated Silicosis: A Systematic Review.

Silicosis is a progressive fibrotic lung disease that is caused by the inhalation of respirable crystalline silica. Due to its high silica content, artificial stone (AS) can become a possible source of hazardous dust exposure for workers that are employed in the manufacturing, finishing, and installing of AS countertops. Therefore, the aim of this review was to verify the association between AS derived silica exposure and silicosis development, and also then define the pathological characteristics of the disease in relation to specific work practices and preventive and protective measures that were adopted in the workplace. A systematic review of articles available on Pubmed, Scopus, and Isi Web of Knowledge databases was performed. Although the characteristics of AS-associated silicosis were comparable to those that were reported for the disease in traditional silica exposure settings, some critical issues emerged concerning the general lack of suitable strategies for assessing/managing silica risks in these innovative occupational fields. Further research that is designed to assess the hazardous properties of AS dusts, levels of exposure in workplaces, and the effectiveness of protective equipment appears to be needed to increase awareness concerning AS risks and induce employers, employees, and all factory figures that are engaged in prevention to take action to define/adopt proper measures to protect the health of exposed workers.

Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway.

Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG. The level of the endocannabinoid 2-arachidonoylglycerol (2-AG) was instead increased in the LEC. Chronic treatment with PEA, starting from when neuropathic pain was fully developed, was able to reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP in SNI wild type, but not in PPARα null, mice. PEA also restored the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis. Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.

d-Aspartic acid ameliorates painful and neuropsychiatric changes and reduces ß-amyloid Aß1-42 peptide in a long lasting model of neuropathic pain.

Depressive symptoms and other neuropsychiatric dysfunctions are common in neurodegenerative disorders, including chronic pain and dementia. A correlation between the ß-amyloid protein accumulation and the development of depression has been suggested, however the underlying mechanisms are unknown. d-Aspartate (d-Asp) is a free d-amino acid found in the mammalian brain and involved in neurological and psychiatric processes, such as cognition and affective disorders. In this study we have investigated the effects of a repeated treatment with d-Asp in a long-lasting (12 months) model of neuropathic pain, the spared nerve injury (SNI), in mice. Specifically, we evaluated i) the pain sensitivity and related emotional/cognitive dysfunctions induced by SNI, ii) possible changes in the ß-amyloid protein accumulation in specific brain regions involved in pain mechanisms ii) possible changes in steroids level in neuropathic animals with or without d-Asp in the same brain areas. SNI mice showed an increase of the insoluble form of Aß1-42 at hippocampal level and displayed cognitive impairments, stereotypical and depressive-like behaviours. d-Asp treatment reduced abnormal behaviours and normalized the ß-amyloid protein expression. Moreover, d-Asp dramatically increased steroids level measured in the prefrontal cortex and in the hippocampus. Our findings provide new insights into pain mechanisms and suggest a possible role of ß-amyloid protein in neuropsychiatric dysfunctions associated with chronic pain.

Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) represents a major public health problem, which is associated with neurological dysfunction. In severe or moderate cases of TBI, in addition to its high mortality rate, subjects may encounter diverse behavioral dysfunctions. Previous reports suggest that an association between TBI and chronic pain syndromes tends to be more common in patients with mild forms of brain injury. Despite causing minimal brain damage, mild TBI (mTBI) often leads to persistent psychologically debilitating symptoms, which can include anxiety, various forms of memory and learning deficits, and depression. At present, no effective treatment options are available for these symptoms, and little is known about the complex cellular activity affecting neuronal activity that occurs in response to TBI during its late phase. Here, we used a mouse model to investigate the effect of Palmitoylethanolamide (PEA) on both the sensorial and neuropsychiatric dysfunctions associated with mTBI through behavioral, electrophysiological, and biomolecular approaches. Fourteen-day mTBI mice developed anxious, aggressive, and reckless behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th day onward. Altered behavior was associated with changes in interleukin 1 beta (IL-1ß) expression levels and neuronal firing activity in the medial prefrontal cortex. Compared with vehicle, PEA restored the behavioral phenotype and partially normalized the biochemical and functional changes occurring at the supraspinal level. In conclusion, our findings reveal some of the supraspinal modifications responsible for the behavioral alterations associated with mTBI and suggest PEA as a pharmacological tool to ameliorate neurological dysfunction induced by the trauma.

D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

FACTOR STRUCTURE AND PSYCHOMETRIC PROPERTIES OF THE INDEX OF TEACHING STRESS-SHORT FORM (ITS-SF).

This study analyses factor structure and psychometric properties of the Italian short version of the Index of Teaching Stress-Short Form (ITS-SF). The original version of the ITS (90 items) was submitted to 567 teachers randomly drawn from a cross-section of school levels. Confirmatory factor analysis to check the factor structure was unsatisfactory, and Cronbach's α (.98) indicated a redundancy of items. Exploratory factor analysis was conducted for each section of the test and cross-loading items were eliminated. The resulting ITS-SF consists of 43 items, tapping eight meaningful and adequately reliable dimensions substantially corresponding to all dimensions measured by the original version of the ITS. The Italian short version of the Index of Teaching Stress constitutes a reliable measure of teacher stress in educative interactions.

Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB1R signaling and anxiety-like behavior.

Endocannabinoids (eCB) are key regulators of excitatory/inhibitory neurotransmission at cannabinoid-1-receptor (CB1 R)-expressing axon terminals. The most abundant eCB in the brain, that is 2-arachidonoylglycerol (2-AG), is hydrolyzed by the enzyme monoacylglycerol lipase (MAGL), whose chronic inhibition in the brain was reported to cause CB1 R desensitization. We employed the MAGL knock-out mouse (MAGL-/-), a genetic model of congenital and sustained elevation of 2-AG levels in the brain, to provide morphological and biochemical evidence for ß-arrestin2-mediated CB1 R desensitization in brain regions involved in the control of emotional states, that is, the prefrontal cortex (PFC), amygdala, hippocampus and cerebellar cortex. We found a widespread CB1 R/ß-arrestin2 co-expression in the mPFC, amygdala and hippocampus accompanied by impairment of extracellular signal-regulated kinase signaling and elevation of vesicular glutamate transporter (VGluT1) at CB1 R-positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB1 R-positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB1 R signaling in MAGL-/- mice was also accompanied by enhanced excitatory drive in the basolateral amygdala (BLA)-mPFC circuit, with subsequent elevation of glutamate release to the mPFC and anxiety-like and obsessive-compulsive behaviors, as assessed by the light/dark box and marble burying tests, respectively. Collectively, these data provide evidence for a ß-arrestin2-mediated desensitization of CB1 R in MAGL-/- mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions. In this study, the authors provide evidence that congenitally enhanced endocannabinoid levels in the neuronal circuits underlying anxiety-like behavioral states (mainly medial prefrontal cortex, amygdala and hippocampus) lead to CB1R desenistization and anxiety and depression. MAGL-/- mice, a model of congenital overactivity of the eCB system, exhibited a compensatory impairment of CB1R signaling in anxiety-associated brain areas and a subsequent change in excitatory/inhibitory tone associated with altered score in the marble burying and light/dark box test, in concomitance with anxiety and depression behavior states. These findings may have potential relevance to the understanding of the neurochemical effects of chronic CB1R overstimulation in cannabis abusers.

Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain.

In humans, affective consequences of neuropathic pain, ranging from depression to anxiety and anhedonia, severely impair quality of life and are a major disease burden, often requiring specific medications. Depressive- and anxiety-like behaviors have also been observed in animal models of peripheral nerve injury. Dysfunctions in central nervous system monoamine transmission have been hypothesized to underlie depressive and anxiety disorders in neuropathic pain. To assess whether these neurons display early changes in their activity that in the long-term might lead to chronicization, maladaptive plasticity and affective consequences, we carried out in vivo extracellular single unit recordings from serotonin neurons in the dorsal raphe nucleus (DRN) and from dopamine neurons in ventral tegmental area (VTA) in the spared nerve injury (SNI) model of neuropathic pain in rats. Extracellular dopamine levels and the expression of dopamine D1, D2 receptors and tyrosine hydroxylase (TH) were measured in the nucleus accumbens. We report that, two weeks following peripheral nerve injury, discharge rate of serotonin DRN neurons and burst firing of VTA dopamine cells are enhanced, when compared with sham-operated animals. We also observed higher extracellular dopamine levels and reduced expression of D2, but not D1, receptors and TH in the nucleus accumbens. Our study confirms that peripheral neuropathy induces changes in the serotonin and dopamine systems that might be the early result of chronic maladaptation to persistent pain. The allostatic activation of these neural systems, which mirrors that already described as a consequence of stress, might lead to depression and anxiety previously observed in neuropathic animals but also an attempt to cope positively with the negative experience.

MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice.

This study investigated the effects of a single administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridinyl-4-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a negative allosteric modulator (NAM) of metabotropic glutamate receptor 7 (mGluR7), on pain and on affective and cognitive behavior in neuropathic mice. The activity of pyramidal neurons in the prelimbic cortex (PLC), which respond to stimulation of the basolateral amygdala (BLA) with either excitation or inhibition, was also investigated. The spared nerve injury (SNI) of the sciatic nerve induced, 14 days after surgery, thermal hyperalgesia and mechanical allodynia, reduced open-arm choice in the elevated plus-maze, increased time of immobility in the tail suspension, and increased digging and burying in the marble burying test. Cognitive performance was also significantly compromised in the SNI mice. Spared nerve injury induced phenotypic changes on pyramidal neurons of the PLC; excitatory responses increased, whereas inhibitory responses decreased after BLA stimulation. mGluR7 expression, mainly associated with vesicular glutamate transporter, increased in the hippocampus and decreased in the BLA, PLC, and dorsal raphe in SNI mice. MMPIP increased thermal and mechanical thresholds and open-arm choice. It reduced the immobility in the tail suspension test and the number of marbles buried and of digging events in the marble burying test. MMPIP also improved cognitive performance and restored the balance between excitatory and inhibitory responses of PLC neurons in SNI mice. 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one, XAP044, another selective mGluR7 NAM, reproduced the effects of MMPIP on thermal hyperalgesia, mechanical allodynia, tail suspension, and marble burying test. Altogether, these findings show that mGluR7 NAMs reduce pain responses and affective/cognitive impairments in neuropathic pain conditions.

A2A adenosine receptor antagonism enhances synaptic and motor effects of cocaine via CB1 cannabinoid receptor activation.

BACKGROUND: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. PRINCIPAL FINDINGS: Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. CONCLUSIONS: The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine.

Loss of striatal cannabinoid CB1 receptor function in attention-deficit / hyperactivity disorder mice with point-mutation of the dopamine transporter.

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.

Higher free D-aspartate and N-methyl-D-aspartate levels prevent striatal depotentiation and anticipate L-DOPA-induced dyskinesia.

In Parkinson's disease (PD) progressive alteration of striatal N-methyl-D-aspartate receptors (NMDARs) signaling has emerged as a considerable factor for the onset of the adverse motor effects of long-term levodopa (l-DOPA) treatment. In this regard, the NMDAR channel blocker amantadine is so far the only drug available for clinical use that attenuates L-DOPA-induced dyskinesia (LID). In this study, we examined the influence of a basal corticostriatal hyper-glutamatergic transmission in the appearance of dyskinesia, using a genetic mouse model lacking D-Aspartate Oxidase (DDO) enzyme (Ddo(-/-) mice). We found that, in Ddo(-/-) mice, non-physiological, high levels of the endogenous free D-amino acids D-aspartate (D-Asp) and NMDA, known to stimulate NMDAR transmission, resulted in the loss of corticostriatal synaptic depotentiation and precocious expression of LID. Interestingly, the block of depotentiation precedes any change in dopaminergic transmission associated to 6-OHDA lesion and l-DOPA treatment. Indeed, lesioned mutant mice display physiological L-DOPA-dependent enhancement of striatal D1 receptor/PKA/protein phosphatase-1 and ERK signaling. Moreover, in line with synaptic rearrangements of NMDAR subunits occurring in dyskinetic animal models, a short L-DOPA treatment produces a dramatic and selective reduction of the NR2B subunit in the striatal post-synaptic fraction of Ddo(-/-) lesioned mutants but not in controls. These data indicate that a preexisting hyper-glutamatergic tone at NMDARs in Ddo(-/-) mice produce abnormal striatal synaptic changes that, in turn, facilitate the onset of LID.

Persistent increase of D-aspartate in D-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay.

The atypical amino acid d-aspartate (d-Asp) occurs at considerable amounts in the developing brain of mammals. However, during postnatal life, d-Asp levels diminish following the expression of d-aspartate oxidase (DDO) enzyme. The strict control of DDO over its substrate d-Asp is particularly evident in the hippocampus, a brain region crucially involved in memory, and highly vulnerable to age-related deterioration processes. Herein, we explored the influence of deregulated higher d-Asp brain content on hippocampus-related functions during aging of mice lacking DDO (Ddo(-/-)). Strikingly, we demonstrated that the enhancement of hippocampal synaptic plasticity and cognition in 4/5-month-old Ddo(-/-) mice is followed by an accelerated decay of basal glutamatergic transmission, NMDAR-dependent LTP and hippocampus-related reference memory at 13/14 months of age. Therefore, the precocious deterioration of hippocampal functions observed in mutants highlights for the first time a role for DDO enzyme in controlling the rate of brain aging process in mammals.