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

Abstract

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.

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

“…For D-Asp, a prominent NMDA receptor-mediated component was already reported in the prefrontal cortical (Errico et al, 2014), striatal (Errico et al, 2008b) and hippocampal (Errico et al, 2008a;Kiskin et al, 1990) neurons. Moreover, in agreement with our data, D-Asp activates mGlu 5 receptors in neonatal cortical and hippocampal neurons (Molinaro et al, 2010).…”

“…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.…”

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

“…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. The presence of enhanced cortico-hippocampal connectivity in a mouse model like Ddo − / − , which shows an overall resiliency to PCP-induced SCZ-like manifestations, is broadly consistent with the impaired cortico-hippocampal brain network organization reported in patients and in preclinical models of SCZ.…”

“…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 .…”

D-Amino Acids in the Nervous and Endocrine Systems

“…Improvement in spatial memory was demonstrated in Ddo knockout mice [77, 78]. Moreover, D-aspartate-treated mice and Ddo knockout mice demonstrated an enhancement of LTP [77–79] and increase in the dendritic length and spine density in neurons in the prefrontal cortex and hippocampus [94]. Therefore, a significant increase in levels of D-aspartate, enhancement of LTP, and increase in the dendritic length and spine density of neurons in adult Ddo knockout mice indicate that D-aspartate might also be generated and function in CNS during adulthood.…”