Increased d-aspartate brain content rescues hippocampal age-related synaptic plasticity deterioration of mice

Errico, Francesco; Nisticò, Robert; Napolitano, Francesco; Mazzola, Carmen; Astone, Dalila; Pisapia, Teresa; Giustizieri, Michela; D’Aniello, Antimo; Mercuri, Nicola Biagio; Usiello, Alessandro

doi:10.1016/j.neurobiolaging.2010.01.002

Cited by 73 publications

(102 citation statements)

References 52 publications

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“…For example, in CA1 hippocampal pyramidal cells, young adult Ddo À/À mice show enhanced NMDA receptor-dependent LTP and have enhanced cognitive properties, improved memory and spatial learning. In the hippocampus and the prefrontal cortex this is accompanied by increases in spine density and dendritic length (Errico et al, 2008a(Errico et al, , 2011b(Errico et al, , 2012(Errico et al, , 2014. In accordance with an abnormally high NMDA receptor transmission, Ddo À/À mice are also characterized by loss of the corticostriatal long-term depression (Errico et al, 2008b(Errico et al, , 2011a(Errico et al, , 2012.…”

Section: Introductionmentioning

confidence: 96%

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

et al. 2016

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Section: Introductionmentioning

confidence: 96%

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

et al. 2016

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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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“…Cognitive function in animal models is usually assessed by electrophysiological analysis of hippocampal synaptic plasticity or behavioural analysis of learning and memory [44][45][46]. Of note, aberrant synaptic plasticity has been observed in experimental models of AD [47][48][49], Parkinson's disease [50], autism spectrum disorders [51] and depression [52].…”

Section: Long-term Potentiation Studies In Experimental Multiple Sclementioning

confidence: 99%

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Nisticò

Mori

Feligioni

et al. 2014

Phil. Trans. R. Soc. B

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Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.

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Increased d-aspartate brain content rescues hippocampal age-related synaptic plasticity deterioration of mice

Cited by 73 publications

References 52 publications

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

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

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

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