A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice.

Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo(-)(/-)), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo(-/-) mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo(-/-) animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by pronounced social and communication deficits and stereotyped behaviours. Recent psychosocial and neuroimaging studies have highlighted reward-processing deficits and reduced dopamine (DA) mesolimbic circuit reactivity in ASD patients. However, the neurobiological and molecular determinants of these deficits remain undetermined. Mouse models recapitulating ASD-like phenotypes could help generate hypotheses about the origin and neurophysiological underpinnings of clinically relevant traits. Here we used functional magnetic resonance imaging (fMRI), behavioural and molecular readouts to probe dopamine neurotransmission responsivity in BTBR T(+) Itpr3(tf)/J mice (BTBR), an inbred mouse line widely used to model ASD-like symptoms owing to its robust social and communication deficits, and high level of repetitive stereotyped behaviours. C57BL/6J (B6) mice were used as normosocial reference comparators. DA reuptake inhibition with GBR 12909 produced significant striatal DA release in both strains, but failed to elicit fMRI activation in widespread forebrain areas of BTBR mice, including mesolimbic reward and striatal terminals. In addition, BTBR mice exhibited no appreciable motor responses to GBR 12909. DA D1 receptor-dependent behavioural and signalling responses were found to be unaltered in BTBR mice, whereas dramatic reductions in pre- and postsynaptic DA D2 and adenosine A2A receptor function was observed in these animals. Overall these results document profoundly compromised DA D2-mediated neurotransmission in BTBR mice, a finding that is likely to have a role in the distinctive social and behavioural deficits exhibited by these mice. Our results call for a deeper investigation of the role of dopaminergic dysfunction in mouse lines exhibiting ASD-like phenotypes, and possibly in ASD patient populations.

Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.

Bimodal effect of D-aspartate on brain aging processes: insights from animal models.

Nowadays it is widely recognized that D-amino acids are present in bacteria as well as in eukaryotes, including mammals. In particular, free D-serine and D-aspartate are found in the brain of mammals. Notably, D-aspartate occurs at substantial levels in the embryo brain to then consistently decrease at post-natal phases. Temporal regulation of D-aspartate content depends on the post-natal onset of D-aspartate oxidase expression, the only known enzyme able to catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds and activates NMDA receptors (NMDARs). To decipher the physiological function of D-aspartate in mammals, in the last years, genetic and pharmacological mouse models with abnormally higher levels of this D-amino acid have been generated. Overall, these animal models have pointed out a significant neuromodulatory role for D-aspartate in the regulation of NMDAR-dependent functions. Indeed, increased content of D-aspartate are able to increase hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory of adult mice. However, if exposure to elevated levels of D-Asp lasts for the entire lifetime of mice, enhancement of synaptic plasticity turns into a dramatic worsening, thus triggering an acceleration of the NMDAR-dependent aging processes in the hippocampus. Nonetheless, administration of D-Asp to old mice can restore the physiological age-related decay of hippocampal NMDA-related LTP. Besides its effect on hippocampus-dependent processes in mouse models, different points of evidence are indicating, today, a potential role for D-Asp in neurologic and psychiatric disorders associated with aberrant signalling of NMDARs.

Consumer and surrogate preferences for a cash option versus traditional services: Florida adults with developmental disabilities.

As long-term service expenditures have risen, policymakers have sought ways to control costs while maintaining consumer satisfaction. Concurrently, there is increasing interest in the disability community in consumer direction. The Cash and Counseling Demonstration and Evaluation (CCDE) seeks to increase consumer direction and control costs by offering a cash allowance and information services to persons with disabilities, enabling them to purchase needed assistance. Because the disability community is composed of diverse subgroups, needs of these consumer communities must be assessed individually. Results from a telephone survey conducted to assess the interest in a cash option for Florida adults with developmental disabilities is presented, the three-state CCDE described, how survey findings can inform consumer information efforts discussed, and policy issues highlighted.

Healthy Start: a comprehensive health education program for preschool children.

BACKGROUND: Healthy Start is a 3-year demonstration and education research project designed to evaluate the effectiveness of a multidimensional cardiovascular (CV) risk reduction intervention in preschool centers over a 3-year period of time. METHODS: Two primary interventions are employed. The first is the preschool food service intervention program designed to reduce the total fat in preschool meals and snacks to less than 30% of calories and reduce the saturated fat to less than 10% of calories. The second major intervention is a comprehensive preschool health education curriculum, focused heavily on nutrition. RESULTS: Effectiveness of the intervention will be determined through evaluation of changes in dietary intake of preschool children at school meals and snacks, especially with respect to intake of total and saturated fat. Evaluation of the education component will include assessment of program implementation by teachers, assessment of changes in nutrition knowledge by preschool children, and assessment of changes in home meals that children consume (total and saturated fat content). Blood cholesterol will be evaluated semiannually to evaluate changes that may be due to modification of dietary intake. Growth and body fatness will also be assessed. CONCLUSIONS: While substantial efforts have targeted CV risk reduction and health education for elementary school children, similar efforts aimed at preschool children have been lacking. The rationale for beginning CV risk reduction programs for preschool children is based upon the premise that risk factors for heart disease are prevalent by 3 years of age and tend to track over time, most commonly hypercholesterolemia and obesity, both related to nutrition. Since the behavioral antecedents for nutritional risk factors begin to be established very early in life, it is important to develop and evaluate new educational initiatives such as Healthy Start, aimed at the primary prevention of cardiovascular risk factors in preschool children. The purpose of this publication is to describe the rationale and methods for the Healthy Start project.

Management of childhood obesity in pediatric practice.

Evaluation of obese children and adolescents in the pediatric office or clinic should include baseline assessment of weight for height and body fatness; rule out endocrine and genetic causes of obesity; and evaluate other health-risk factors, such as those for cardiovascular disease, cancer, diabetes, and hypertension. Treatment of obesity is most successful if realistic goals are set; a balanced low-fat/high-fiber diet is stressed; a safe rate of weight loss of 1 to 2 pounds per week is achieved through a moderate reduction of caloric intake (approximately 20-25% decrease); increased physical activity is stressed as much as diet; parental support is strong; and behavior therapy is provided during the course of treatment to help both child and parent achieve the diet, exercise, and behavior goals.

Determining consumer preferences for a cash option: Arkansas survey results.

As long-term care (LTC) expenditures have risen, policymakers have sought ways to control costs while maintaining consumer satisfaction. Concurrently, there is increasing interest within the aging and disability communities in consumer-directed care. The Cash and Counseling Demonstration and Evaluation (CCDE) seeks to increase consumer direction and control costs by offering a cash allowance and information services to persons with disabilities, enabling them to purchase needed assistance. The authors present results from a telephone survey conducted to assess consumer preferences for a cash option in Arkansas and describe how findings from the four-State CCDE can inform consumer information efforts and policymakers.