Alessandro Usiello
Potential involvement of the amino acid D-aspartate in developmental processes mediated by NMDA receptors and relevant to schizophrenia

Alessandro Usiello


Full Professor of Clinical Biochemistry and Clinical Molecular Biology. The University of Campania, L. Vanvitelli, Caserta, Italy.

Member of SINS (Italian Society for Neuroscience)

Full Professor of  Clinical Biochemistry and Clinical Molecular Biology  at University of Campania Luigi Vanvitelli, Caserta, and Principal Investigator of the Behavioural Neuroscience Laboratory at Ceinge Biotecnologie Avanzate, Naples. During his training in the laboratory of Psychobiology and Neuropharmacology of University of Roma La Sapienza and Istituto Superiore di Sanità, Prof. Usiello acquired basic notions on rodents’ behavior. As PhD student in Molecular Biology at Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) in Strasbourg, he worked on the functional characterization of the in vivo and in vitro features of the two different isoforms of the Dopamine D2 receptor (D2R). His research activity was published in three peer-reviewed journals as Nature, Journal of Neuroscience and PNAS, where he contributed as first author. He spent one year, as researcher at Cellular Biology Institute of National Research Council (CNR) and, in this period, he started a collaboration with Prof. Antonio Simeone at King’s College of London. After that, he worked in the Molecular Pharmacology Laboratory directed by Prof. Gilberto Fisone, at Karolinska Institutet, Stockholm, Sweden.

Thanks to a "Junior Principal Investigator Grant", financed by Ministero Italiano dell’Università e della Ricerca, in 2005 Prof. Usiello moved from Sweden to Italy, at Ceinge, where he founded his research group. Since the beginning, he worked in scientific research fields covering different aspects of neuroscience. As Senior Principal Investigator at Ceinge he established a multidisciplinary network international collaborators, including the neuroscientist Prof. Solomon Snyder at John Hopkins Medical School, Baltimore. Recently, he started a tight collaboration with Prof. Subramaniam at Scripps Research Institute in the Department of Neuroscience, Jupiter, Florida, and Prof. Noriko Fuji, at Kyoto University, Osaka, Japan. Overall, his scientific achievements led to the publication of about 100 original papers in top-ranking peer-reviewed journals, including Nature Neuroscience, The Journal of Neuroscience, PNAS, American Journal of Psychiatry, EMBO Reports, Brain. Alongside his research activity, he got the position of Associate Professor at University of Molise in 2006, and then, in 2009, at University of Campania Luigi Vanvitelli. Prof. Usiello is also Professor of PhD program at European School of Molecular Medicine, Milan, Second University of Rome Tor Vergata, and University of Campania Luigi Vanvitelli.

Curriculum178.07 KB

Free D-amino acid, D-aspartate, is present at high levels in the developing brain and acts as an agonist at NMDA receptors. Deregulation of its metabolism may impact on neurodevelopmental disorders; indeed reduced D-aspartate levels have been found in the brain of patients with schizophrenia. In the light of this background, it has been proposed a role for D-aspartate as a novel signaling molecule involved in the embryonic glutamatergic neurotransmission underpinning the physiological brain development and function. In order to clarify the biological significance of D-aspartate in the developing mammalian brain, the research group directed by Prof. Usiello is carrying out the behavioral characterization of a novel mouse model in which the expression of D-aspartate oxidase, the enzyme responsible for the degradation of D-aspartate, is anticipated in the brain since the embryonic stages. Specifically, Prof. Usiello’s group is exploring if the absence of D-aspartate causes anomalies in sensorimotor gating, attentional, cognitive and social behavior, which are relevant to psychiatric-like disorders. Prof Usiello is also studying the neurochemical and molecular consequences of embryonic D-aspartate depletion in the mouse brain and the role of this neurotransmitter in regulating cerebral development and adult brain morphology. Moreover, his group is studying the influence of early perturbation in D-Asp metabolism on the expression of genes encoding proteins involved in the formation and function of glutamatergic synapses.

Prof. Usiello’s group has been working for about 15 years on the potential role of the small GTP-binding protein, Rhes, in the pathophysiology of the corpus striatum, where it is highly expressed. Striatum represents the largest nucleus of the basal ganglia, involved in the modulation of motor functions and several aspects of cognition, motivation, reinforcement and reward perception, whose abnormalities rely on a variety of psychomotor disorders, ranging from neurological pathologies, such as Parkinson’s disease (PD), to psychiatric disorders, including schizophrenia and drug addiction. Thus, Prof. Usiello took advantage of a genetically modified mouse model (KO), characterized by the constitutive deletion of the Rhes gene. Results so far obtained by his group documented, for the first time, that, besides rodents, Rhes is expressed in virtually all dopaminoceptive neurons, namely medium-sized spiny neurons, of both human and non-human primate striata, where it affects dopamine (DA)-and adenosine-dependent transmission. Accordingly, he documented that Rhes KO animals displayed alterations in phenotypes reminiscent of psychiatric illness in humans, including deficits in prepulse inhibition of the startle reflex and, most interestingly, a striking enhancement of behavioral responses elicited by caffeine, phencyclidine, amphetamine and cocaine as well. Moreover, based on the notion that Rhes can interact with and activate striatal mTORC1, one of the key players in L-DOPA-induced dyskinesia in rodent PD models, he found that lack of Rhes attenuated such motor disturbances in 6-OHDA-lesioned Rhes KO mice. In line with a potential role of Rhes in the modulation of dopamine innervation, Prof. Usiello find out a significant downregulation of Rhes mRNA levels in the putamen of PD non-human primate model, treated with the neurotoxin MPTP. Overall, these data point out that Rhes is emerging as an important player in orchestrating striatal physiological processes of potential interest for both psychiatric and neurological disorders.


Research lines
  1. Role of the amino acid D-aspartate in developmental processes mediated by NMDA receptors and relevant to schizophrenia dependent upon glutamatergic neurotransmission in embryonic stages.
  2. Physiological relevance of the enzyme responsible for the degradation of D-aspartate, D-aspartate oxidase, in the mammalian brain during aging.
  3.  Role of the small GTP-binding protein Rhes in modulating behavioral and molecular responses following acute and chronic cocaine treatment.
Research Group

             Nuzzo Tommaso, Post Doc

             Di Maio Anna, PhD student

             De Rosa Arianna, PhD student

             Garofalo Martina, graduate student

             D’Alessio Pasquale, graduate student

Most relevant publications

RasGRP1 is a Causal Factor in the Development of Levodopa-induced dyskinesia in Parkinson Disease. Eshragi M, Nimrod Ramirez Jarquin U, Shahani N, Nuzzo T, De Rosa A, Swarnkar S, Galli N, Rivera O, Tsaprailis G, Scharager-Tapia C, Crynen G, Li Q, Thiolat ML, Bezard E, Usiello A, Subramaniam S. Science Advances, 2020 IN PRESS

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients. Nuzzo T, Sacchi S, Errico F, Keller S, Palumbo O, Florio E, Punzo D, Napolitano F, Copetti M, Carella M, Chiariotti L, Bertolino A, Pollegioni L, Usiello A. NPJ Schizophrenia, 2017

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. Sacchi S, Novellis V, Paolone G, Nuzzo T, Iannotta M, Belardo C, Squillace M, Bolognesi P, Rosini E, Motta Z, Frassineti M, Bertolino A, Pollegioni L, Morari M, Maione S, Errico F, Usiello A Scientific Report, 2017

Age-Related Changes in D-Aspartate Oxidase Promoter Methylation Control Extracellular D-Aspartate Levels and Prevent Precocious Cell Death during Brain Aging. Punzo D, Errico F, Cristino L, Sacchi S, Keller S, Belardo C, Luongo L, Nuzzo T, Imperatore R, Florio E, De Novellis V, Affinito O, Migliarini S, Maddaloni G, Sisalli M. J, Pasqualetti M, Pollegioni L, Maione S, Chiariotti L, Usiello A. The Journal of Neuroscience, 2016; 36(10):3064-78.

Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Subramaniam S, Napolitano F, Mealer RG, Kim S, Errico F, Barrow R, Shahani N, Tyagi R, Snyder SH, Usiello A. Nature Neuroscience, 2011; 15(2):191-3.