Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission

Abstract

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Prediction of complex phenotypes using theDrosophilametabolome

“…Each NMR feature (14,440 in total) was treated as a quantitative trait. For each NMR feature, we fitted a linear mixed model to partition the total phenotypic variation (i.e.…”

“…Challenges with using DNA sequence variation to predict variation at the organismal phenotypic level have sparked an interest in using endophenotypes, such as transcript, protein or metabolite levels as predictors of complex functional phenotypes. [14][15][16][17] Endophenotypes influence and regulate the functional phenotype and in contrast to the genotype, which is fixed in an individual's lifetime, they are governed by interactions between the genome of an individual, and internal and external influences that range from the cellular level and to the wealth of external biotic and abiotic factors an individual is exposed to in its environment. Thus, endophenotypes have been proposed to constitute proximal links between variation at the genome level and the organismal phenotype and they may provide more accurate predictors of the functional phenotype compared to the genotype.…”

Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry

“…Biochemical markers are intermediate to the outward phenotype and the underlying biology of aggression. They can aid in elucidating the causes and (patho) physiology of aggressive behavior [James et al, ; Scoriels et al, ]. One of the promises of biochemical studies of central nervous system diseases is the development of biochemically based biomarkers [Kaddurah‐Daouk and Krishnan, ].…”

NMDA receptor blockade causes selective prefrontal disinhibition in a roving auditory oddball paradigm

“…N-methyl-D-aspartate receptor (NMDAR) hypofunction is believed to be one of the primary causes of schizophrenia, a common neuropsychiatric condition (1)(2)(3)(4)(5). In healthy human subjects, pharmacological interventions such as exposure to ketamine, which acts as a non-competitive NMDAR antagonist, can in part reproduce a recognisable set of symptoms and signs (such as delusional beliefs, hallucinations, working memory deficits and social withdrawal), and electrophysiological brain abnormalities associated with schizophrenia (6)(7)(8).…”