Glutamate and modeling of schizophrenia symptoms: Review of our Findings: 1990–2014

Abstract

In the early 90s, we studied the role of perception disturbances in schizophrenia in our first clinical approaches, using the Bender test in schizophrenic patients. Results were clear, showing a shape discrimination failure. Following this initial results, we reproduced nuclear symptoms of schizophrenia in animal models, showing that perceptual disturbances, acquisition disturbances, decrease in affective levels and working memory disturbances can be induced by specific N-methyl-D-aspartic acid (NMDA) glutamatergic blockade within the nucleus accumbens septi (NAS). We studied also another glutamatergic and dopaminergic drugs, finding that a decrease in glutamatergic transmission within NAS led to cognitive disturbances and affective flattening. An increase in glutamatergic transmission fully enhances cognition in the tasks used. Dopaminergic D-2 antagonists partially improved cognition. Our results link the proposed corticostriatal dysfunction with the thalamocortical disturbances underlying perceptual problems, but also influencing affective levels and cognitive variables. According to our translational findings, core schizophrenia symptoms may be translationally reproduced antagonizing NMDA receptors within NAS, and improved blocking the glutamate auto-receptor. Dopaminergic transmission appears to have a role in therapeutic but not in the early pathophysiology of schizophrenia.

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

“…Within this framework, the PPI of the startle reflex is one of the most frequently used crossspecies paradigm to evaluate the sensorimotor gating response, known to be disrupted in schizophrenia, and proposed as a candidate neurophysiological endophenotype of this psychiatric disorder (Gottesmann, 2003). In line with the evidence that psychotomimetic drugs, such as Amph and PCP, trigger PPI deficits in both animals and humans, administration of these drugs represents the most widely validated experimental strategy to model schizophrenia-like symptoms in rodents (Braff et al, 2001;Brisch et al, 2014;Gargiulo and Landa De Gargiulo, 2014;Jones et al, 2011). Based on this consideration, in the attempt to move Rasd2 functional characterization from human to mouse, we evaluated whether lack of this GTPase in mutants influences sensorimotor gating responses in drug-free condition and after Amph or PCP treatment.…”

Constitutive loss and acute pharmacological manipulation of ErbB4 signaling do not affect attention and inhibitory control in mice

“…Typical symptoms arise during adolescence or young adulthood, and are classically divided in positive and negative symptoms, which range from delusions and hallucinations to affective flattening and social withdrawal. Recently, cognitive symptoms, such as deficits in executive functions, have been implicated in the disease (Bowie & Harvey ; Gargiulo & Landa De Gargiulo ; G. Orellana & Slachevsky ). It is reported that mild cognitive deficits are present in first‐episode patients, in adolescents with a higher risk of developing the disease, and in first‐degree relatives of affected people.…”

“…Typical symptoms arise during adolescence or young adulthood, and are classically divided in positive and negative symptoms, which range from delusions and hallucinations to affective flattening and social withdrawal. Recently, cognitive symptoms, such as deficits in executive functions, have been implicated in the disease (Bowie & Harvey 2006;Gargiulo & Landa De Gargiulo 2014;G. Orellana & Slachevsky 2013).…”

BDNF Serum Levels are Associated With White Matter Microstructure in Schizophrenia - A Pilot Study

“…Through the TrkB receptor cascade, BDNF stimulates long time potentiation (LTP) in hippocampal neurona, which, in turn, is well known to play a key role in learning and memory (92). In addition, modification of glutamate levels influences characteristic positive and negative symptoms as well as disturbances in working memory (93).…”