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ABSTRACT: Free D-aspartate (D-Asp) occurs in substantial amounts in the brain at the embryonic phase and in the first few postnatal days, and strongly decreases in adulthood. Temporal reduction of D-Asp levels depends on the postnatal onset of D-aspartate oxidase (DDO) activity, the only enzyme able to selectively degrade this D-amino acid. Several results indicate that D-Asp binds and activates N-methyl-D-aspartate receptors (NMDARs). Accordingly, recent studies have demonstrated that deregulated, higher levels of D-Asp, in knockout mice for Ddo gene and in D-Asp-treated mice, modulate hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory. Moreover, similarly to D-serine, administration of D-Asp to old mice is able to rescue the physiological age-related decay of hippocampal LTP. In agreement with a neuromodulatory action of D-Asp on NMDARs, increased levels of this D-amino acid completely suppress long-term depression at corticostriatal synapses and attenuate the prepulse inhibition deficits produced in mice by the psychotomimetic drugs, amphetamine and MK-801. Based on the evidence which points to the ability of D-Asp to act as an endogenous agonist on NMDARs and considering the abundance of D-Asp during prenatal and early life, future studies will be crucial to address the effect of this molecule in the developmental processes of the brain controlled by the activation of NMDARs.
Amino Acids 08/2012; 43(5):1861-71. · 3.25 Impact Factor
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ABSTRACT: L-DOPA-induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes(-/-) mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.
Nature Neuroscience 12/2011; 15(2):191-3. · 15.53 Impact Factor
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ABSTRACT: Until recently, free d-amino acids were thought to be involved only in bacterial physiology. Nevertheless, today there is evidence that D-serine, by acting as co-agonist at NMDARs, plays a role in controlling neuronal functions in mammals. Besides D-serine, another D-amino acid, D-aspartate (D-Asp), is found in the mammalian brain with a temporal gradient of occurrence: high in embryo and low in adult. In this study, we demonstrate that D-Asp acts as an endogenous NMDAR agonist, since it triggers currents via interaction with each of NR2A-D receptor subunits. According to its pharmacological features, we showed that oral administration of D-Asp strongly enhances NMDAR-dependent LTP in adulthood and, in turn, completely rescues the synaptic plasticity decay observed in the hippocampus of aged animals. Therefore, our findings suggest a tantalizing hypothesis for which this in-embryo-occurring D-amino acid, when "forced" over its physiological content, may disclose plasticity windows inside which it counteracts the age-related reduction of NMDAR signaling.
Neurobiology of aging 12/2011; 32(12):2229-43. · 5.94 Impact Factor
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ABSTRACT: 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.
Neurobiology of aging 11/2011; 32(11):2061-74. · 5.94 Impact Factor
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Francesco Errico,
Alessandra Bonito-Oliva,
Vincenza Bagetta,
Daniela Vitucci,
Rosaria Romano,
Elisa Zianni,
Francesco Napolitano,
Silvia Marinucci,
Monica Di Luca,
Paolo Calabresi,
Gilberto Fisone,
Manolo Carta,
Barbara Picconi,
Fabrizio Gardoni,
Alessandro Usiello
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ABSTRACT: 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.
Experimental Neurology 09/2011; 232(2):240-50. · 4.70 Impact Factor
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Francesco Napolitano,
Alessandra Bonito-Oliva,
Mauro Federici,
Manolo Carta, Francesco Errico,
Salvatore Magara,
Giuseppina Martella,
Robert Nisticò,
Diego Centonze,
Antonio Pisani,
Howard H Gu,
Nicola B Mercuri,
Alessandro Usiello
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ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.
Journal of Neuroscience 08/2010; 30(33):11043-56. · 7.11 Impact Factor
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ABSTRACT: Total concentrations of thyroid hormones T(3) and T(4), and of their free forms, FT(3) and FT(4), D-aspartic acid (D-Asp), D-aspartate oxidase (D-AspO), D-aspartate racemase, H(2)O(2), and ROS (reactive oxygen species) were determined in rats and mice. T(3) and T(4) were 1 and 50 ng/ml, respectively, in serum, and 750 and 40000 ng/g, respectively, in thyroid. Concentrations of the free forms FT(3) and FT(4) were ca. 250 times lower than their respective total concentrations. The endogenous content of D-Asp in thyroid gland was ca. 100 nmol/g tissue, whereas the activity of D-AspO was ca. 80 units/mg thyroid, and that of D-aspartate racemase was ca. 15 units/mg thyroid. H(2)O(2) Concentration in rat and mouse thyroid gland was ca. 290 pmol/g thyroid, and the concentration of ROS was ca. 10 pmol/DCF/min/mg protein. H(2)O(2) is essential for the iodination of the tyrosyl residues to produce mono- and diiodotyrosine that are the precursors for the synthesis of T(3) and T(4). Production of H(2)O(2) in thyroid glands occurs by oxidation of endogenous D-Asp by D-AspO (D-Asp+O(2)+H(2)O-->alpha-oxaloacetate+NH(3)+H(2)O(2)). D-Aspartate racemase catalyzes the in vivo production of D-Asp from L-Asp. Thus, interaction of endogenous D-Asp, D-AspO, and D-aspartate racemase in thyroid gland constitutes an additional biochemical pathway for the production of H(2)O(2) and consequently for the synthesis of thyroid hormones.
Chemistry & Biodiversity 06/2010; 7(6):1467-78. · 1.80 Impact Factor
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Francesco Napolitano,
Massimo Pasqualetti,
Alessandro Usiello,
Emanuela Santini,
Giulia Pacini,
Giuseppe Sciamanna, Francesco Errico,
Annalisa Tassone,
Valeria Di Dato,
Giuseppina Martella,
Dario Cuomo,
Gilberto Fisone,
Giorgio Bernardi,
Georgia Mandolesi,
Nicola B Mercuri,
David G Standaert,
Antonio Pisani
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ABSTRACT: DYT1 dystonia is an inherited disease linked to mutation in the TOR1A gene encoding for the protein torsinA. Although the mechanism by which this genetic alteration leads to dystonia is unclear, multiple lines of clinical evidence suggest a link between dystonia and a reduced dopamine D2 receptor (D2R) availability. Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1 dystonia mutation. Electrophysiological recordings from nigral dopaminergic neurons showed a normal responsiveness to D2-autoreceptor function. Conversely, postsynaptic D2R function in hMT mice was impaired, as suggested by the inability of a D2R agonist to re-establish normal corticostriatal synaptic plasticity and supported by the reduced sensitivity to haloperidol-induced catalepsy. Although an in situ hybridization analysis showed normal D1R and D2R mRNA expression levels in the striata of hMT mice, we found a significant decrease of D2R protein, coupled to a reduced ability of D2Rs to activate their cognate Go/i proteins. Of relevance, we found that pharmacological blockade of adenosine A2A receptors (A2ARs) fully restored the impairment of synaptic plasticity observed in hMT mice. Together, our findings demonstrate an important link between torsinA mutation and D2R dysfunction and suggest that A2AR antagonism is able to counteract the deficit in D2R-mediated transmission observed in mutant mice, opening new perspectives for the treatment of this movement disorder.
Neurobiology of Disease 03/2010; 38(3):434-45. · 5.40 Impact Factor
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Valentina De Chiara, Francesco Errico,
Alessandra Musella,
Silvia Rossi,
Giorgia Mataluni,
Lucia Sacchetti,
Alberto Siracusano,
Maura Castelli,
Francesca Cavasinni,
Giorgio Bernardi,
Alessandro Usiello,
Diego Centonze
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ABSTRACT: The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2009; 35(2):374-87. · 6.99 Impact Factor
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ABSTRACT: Within the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain.
Reviews in the neurosciences 01/2009; 20(5-6):429-40. · 2.41 Impact Factor
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ABSTRACT: Since their discovery in the mammalian CNS, D-aspartate and D-serine have aroused a strong interest with regard to their role as putative neuromodulatory molecules. Whereas the functional role of D-serine as an endogenous coagonist of NMDA receptors (NMDARs) has been elucidated, the biological significance of D-aspartate in the brain is still mostly unclear. In the present study, we demonstrated that nonphysiological high levels of D-aspartate (1) increased in vivo NMDAR activity, (2) attenuated prepulse inhibition deficits induced by amphetamine and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate], (3) produced striatal adaptations of glutamate synapses resembling those observed after chronic haloperidol treatment, and (4) enhanced hippocampal NMDAR-dependent memory. This evidence was obtained using two different experimental strategies that produced an abnormal increase of endogenous D-aspartate levels in the mouse: a genetic approach based on the targeted deletion of the D-aspartate oxidase gene and a pharmacological approach based on oral administration of D-aspartate. This work provides in vivo evidence of a neuromodulatory role exerted by D-aspartate on NMDAR signaling and raises the intriguing hypothesis that also this D-amino acid, like D-serine, could be used as a therapeutic agent in the treatment of schizophrenia-related symptoms.
Journal of Neuroscience 11/2008; 28(41):10404-14. · 7.11 Impact Factor
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Francesco Errico,
Robert Nisticò,
Giuseppe Palma,
Mauro Federici,
Andrea Affuso,
Elisa Brilli,
Enza Topo,
Diego Centonze,
Giorgio Bernardi,
Yuri Bozzi,
Antimo D'Aniello,
Roberto Di Lauro,
Nicola B Mercuri,
Alessandro Usiello
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ABSTRACT: In the present study, we demonstrate a direct role for d-aspartate in regulating hippocampal synaptic plasticity. These evidences were obtained using two different experimental strategies which enabled a non-physiological increase of endogenous d-aspartate levels in the mouse hippocampus: a genetic approach based on the targeted deletion of d-aspartate oxidase gene and another based on the oral administration of d-aspartate. Overall, our results indicate that increased d-aspartate content does not affect basal properties of synaptic transmission but enhances long-term potentiation in hippocampal slices from both genetic and pharmacological animal models. Besides electrophysiological data, behavioral analysis suggests that altered levels of d-aspartate in the hippocampus do not perturb basal spatial learning and memory abilities, but may selectively interfere with the dynamic NMDAR-dependent processes underlying cognitive flexibility.
Molecular and Cellular Neuroscience 03/2008; 37(2):236-46. · 3.66 Impact Factor
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Francesco Errico,
Emanuela Santini,
Sara Migliarini,
Anders Borgkvist,
Diego Centonze,
Valentina Nasti,
Manolo Carta,
Valentina De Chiara,
Chiara Prosperetti,
Daniela Spano,
Denis Herve,
Massimo Pasqualetti,
Roberto Di Lauro,
Gilberto Fisone,
Alessandro Usiello
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ABSTRACT: Rhes is a small GTP-binding protein prominently localized in the striatum. Previous findings obtained in cell culture systems demonstrated an involvement of Rhes in cAMP/PKA signalling pathway, at a level proximal to the activation of heterotrimeric G-protein complex. However, its role in the striatum has been, so far, only supposed. Here we studied the involvement of Rhes in dopaminergic signalling, by employing mice with a null mutation in the Rhes gene. We demonstrated that the absence of Rhes modulates cAMP/PKA signalling in both striatopallidal and striatonigral projection neurons by increasing Golf protein levels and, in turn, influencing motor responses challenged by dopaminergic agonist/antagonist. Interestingly, we also show that Rhes is required for a correct dopamine-mediated GTP binding, a function mainly associated to stimulation of dopamine D2 receptors. Altogether, our results indicate that Rhes is an important modulator of dopaminergic transmission in the striatum.
Molecular and Cellular Neuroscience 03/2008; 37(2):335-45. · 3.66 Impact Factor
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ABSTRACT: Free D-aspartic acid and NMDA are present in the mammalian central nervous system and endocrine glands at significant concentrations, but their physiological role is still matter of debate. The only enzyme known to metabolize in vitro selectively these D-amino acids is D-aspartate oxidase (DDO). To clarify the role in vivo of the enzyme, we generated mice with targeted deletion of Ddo gene by homologous recombination. Mutated animals showed increased amounts of both D-aspartic acid and NMDA in all tissues examined demonstrating a physiological role of DDO in the regulation of their endogenous levels.
Gene 07/2006; 374:50-7. · 2.34 Impact Factor
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Francesco Errico,
Robert Nistico,
Antimo D'Aniello,
Sandra Sivilia,
Michela Giustizieri,
Francesco Napolitano,
Enza Topo,
Giorgio Bernardi,
Laura Calza,
Nicola Mercuri,
Alessandro Usiello
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ABSTRACT: In the present study, we demonstrated that D-aspartate acts as an _in vitro_ and _in vivo_ neuromodulatory molecule upon hippocampal NMDAR transmission. Accordingly, we showed that this D-amino acid, widely expressed during embryonic phase, was able to strongly influence hippocampus-related functions at adulthood. Thus, while up-regulated levels of D-aspartate increased LTP and spatial memory in four-month old adult mice, the prolonged deregulation of this molecule in thirteen-month old animals induced a substantial acceleration of age-dependent decay of synaptic plasticity and cognitive functions. Moreover, we highlighted a role for D-aspartate in enhancing NMDAR-dependent synaptic plasticity through an inducible "turn-on/turn-off-like mechanism". Strikingly, we also showed that D-aspartate, when administered to aged mice, strongly rescued their physiological synaptic decay and attenuated their cognitive deterioration. In conclusion, our data suggest a tantalizing hypothesis for which this in-embryo-occurring D-amino acid, might disclose plasticity windows in the aging brain.
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