Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Errico, Francesco; Nisticò, Robert; Palma, Giuseppe; Federici, Mauro; Affuso, Andrea; Brilli, Elisa; Topo, Enza; Centonze, Diego; Bernardi, Giorgio; Bozzi, Yuri; D’Aniello, Antimo; Lauro, Roberto Di; Mercuri, Nicola Biagio; Usiello, Alessandro

doi:10.1016/j.mcn.2007.09.012

Cited by 82 publications

(118 citation statements)

References 48 publications

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“…LTP was induced by conventional TBS applied to the Schaffer collateral-CA1 synapses TBS (4 trains of 5 pulses at a frequency of 100 Hz, with an intertrain interval of 200 ms) (Errico et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

Synaptic Plasticity and PDGF Signaling Defects Underlie Clinical Progression in Multiple Sclerosis

et al. 2013

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Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that plateletderived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1)

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Section: Methodsmentioning

confidence: 99%

Synaptic Plasticity and PDGF Signaling Defects Underlie Clinical Progression in Multiple Sclerosis

et al. 2013

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“…D-Aspartate levels are high in the embryonic phase and dramatically decrease during postnatal life, in concomitance with increased expression of D-aspartate oxidase (DDO), the enzyme responsible for its deg- radation (Schell et al, 1997;Errico et al, 2006;Huang et al, 2006). In contrast to D-serine, now well characterized for its implication in NMDAR-dependent functions, the role of D-aspartate in the CNS remains elusive.We have shown previously that D-aspartate enhances hippocampal NMDAR-dependent long-term potentiation (LTP) (Errico et al, 2008a). In the present work, we examined whether higher levels of this in-embryo-occurring molecule might increase glutamatergic transmission and exert antipsychotic effects in adult animals.…”

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confidence: 91%

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

et al. 2008

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IntroductionSchizophrenia (SCZ) is a severe mental disorder afflicting ϳ1% of the population worldwide. Despite decades of intensive research, the precise etiology of this devastating mental illness remains, so far, an unresolved puzzle (Sawa and Snyder, 2002). It has been proposed that dysfunction of dopaminergic neurotransmission occurs in SCZ patients (Snyder, 1976); however, a large body of evidence recently proposed that abnormal serotonergic and glutamatergic neurotransmission might also be implicated in the pathophysiological processes leading to the development of schizophrenia (González-Maeso et al., 2008). Compelling evidence from genetic, brain imaging, and clinical studies strongly suggests that psychotic symptoms might be associated with a persistent hypoglutamatergic transmission involving reduced NMDA receptor (NMDAR) activation (Tsai and Coyle, 2002). This hypothesis is mainly based on two fundamental observations: first, administration to healthy subjects of noncompetitive NMDAR antagonists, such as phencyclidine (PCP) or ketamine, results in severe mental symptoms resembling those of schizophrenic patients; second, administration of PCP to psychotic patients exacerbates positive and negative symptoms and worsens their cognitive functions (Javitt and Zukin, 1991;Olney and Farber, 1995). Together, these findings suggest that interventions able to enhance NMDAR transmission might be beneficial for the treatment of SCZ (Kristiansen et al., 2007). In particular, administration of D-serine to clozapine-treated patients ameliorates their positive, negative, and cognitive deficits (Tsai et al., 1999).D-Serine is a D-amino acid occurring in the mammalian forebrain throughout postnatal lifetime (Schell et al., 1995), which acts as an endogenous ligand at strychnine-insensitive glycinebinding site of NMDAR (Martineau et al., 2006). The striking discovery that D-serine could have therapeutic efficacy led to intensive investigations of the possible central functions of "unusual" free D-amino acids. Another D-amino acid, named D-aspartate, occurs in the mammalian brain. D-Aspartate levels are high in the embryonic phase and dramatically decrease during postnatal life, in concomitance with increased expression of D-aspartate oxidase (DDO), the enzyme responsible for its deg- radation (Schell et al., 1997;Errico et al., 2006;Huang et al., 2006). In contrast to D-serine, now well characterized for its implication in NMDAR-dependent functions, the role of D-aspartate in the CNS remains elusive.We have shown previously that D-aspartate enhances hippocampal NMDAR-dependent long-term potentiation (LTP) (Errico et al., 2008a). In the present work, we examined whether higher levels of this in-embryo-occurring molecule might increase glutamatergic transmission and exert antipsychotic effects in adult animals. Using genetic and pharmacological interventions able to enhance D-aspartate levels, we tested the ability of this D-amino acid to modulate cognition and gating abilities, which are thought, when altered, to be in...

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“…[46][47][48] We performed a battery of molecular and behavioral tests that revealed a preserved D2R neurotransmission in Ddo − / − mice, thus corroborating a glutamatergic origin for the different responsivity to PCP observed in Ddo − / − mice (see Supplementary Information and Supplementary Figure S2). fMRI response induced by PCP in Ddo − / − mice Because D-Asp can modulate NMDAR-related functions, [18][19][20][21]38 we used Ddo − / − mice to assess whether genetically driven D-Asp elevation can modulate the aberrant neurofunctional cascade underlying the psychotomimetic effect of PCP. To this purpose, we used fMRI to map the neural substrates recruited by a subanesthetic dose of PCP (intravenous 1 mg kg − 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…This effect is consistent with previous imaging work showing that pharmacological potentiation of NMDAR function by D-Ser, can effectively inhibit the hyperglutamatergic state produced by NMDAR antagonism 32 and modulate psychosis-related neurocircuits. Interestingly, oral supplementation of a neurobiologically active dose of D-Asp to adult C57BL/6 mice 18,19,21,22 failed to inhibit PCP-induced behavioral or functional responses. These findings point at a putative .…”

Section: Discussionmentioning

confidence: 99%

“…25 Interestingly, although the strength of hippocampal-frontal connectivity was similar in the two genotypes, our rsfMRI measurements suggest that elevated DAsp levels can reshape the connectional profile of the hippocampus, resulting in stronger and more widespread peri-hippocampal and parietal-hippocampal connectivity in knockout brains. A role for embryonic and perinatal D-Asp elevation in modeling the connectivity of hippocampal regions is not surprising in the light of the ability of this D-amino acid to promote hippocampal synaptic plasticity, 18,20,21,24 dendritic length and spine density in adulthood. 22 Our data suggest that this feature can alter the connectional profile of this region with neighboring and longrange cortical areas.…”

Section: Discussionmentioning

confidence: 99%

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A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Squillace

Errico

D’Argenio

et al. 2015

European Psychiatry

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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.

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Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Cited by 82 publications

References 48 publications

Synaptic Plasticity and PDGF Signaling Defects Underlie Clinical Progression in Multiple Sclerosis

Synaptic Plasticity and PDGF Signaling Defects Underlie Clinical Progression in Multiple Sclerosis

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

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