T65 - The Influence Of The Glutamatergic System On Cognition In Schizophrenia: A Systematic Review

Abstract

Background Patients with schizophrenia have been estimated to be one to two standard deviations below the scores of healthy controls in terms of cognitive function. Cognitive performance is also impaired in unaffected biological relatives compared to the general population, indicating a genetic contribution to the cognitive impairment. It has been suggested that the glutamatergic system influences cognition and several investigations have explored the relationship between glutamate and cognitive deficits in schizophrenia. However, previous literature indicating a role of the glutamatergic system in cognitive deficits in schizophrenia has been inconclusive. The aim of this study was to systematically review candidate gene studies influencing the glutamatergic pathway and explore the impact on cognition in schizophrenia. Methods 11 relevant candidate gene studies were identified through systematic search following PRISMA guidelines and were reviewed. Ovid MEDLINE, PsychINFO and EMBASE were searched using the following truncation keyword search terms ‘schizophrenia’, ‘glutamat’, ‘cognit’, ‘adult’, ‘human’, ‘patient’ and ‘control.’ To be included, studies must have observed at least one objective measure of cognitive performance in patients with schizophrenia and had to be candidate gene studies focused on the glutamatergic pathway. Animal studies and studies that did not have a schizophrenia or schizoaffective patient study group were excluded. Results Results were examined according to cognitive domain. Of the cognitive domains observed, memory and working memory were most consistently influenced by genetic variation along the glutamatergic pathway. DTNBP1 were associated with verbal and visual memory and working memory performance (n = 565). GRM3 was significantly associated with episodic memory (n = 508). DTNBP1 is involved in the storage and release of GRM3, which encodes mGlu3 (shown to modulate glutamate neurotransmission and synaptic plasticity). G72 activates DAAO, which is involved in the metabolism of D-serine and was significantly associated with episodic memory and working memory (n = 292). NRG1, ErbB4 and AKT1 genes were significantly associated with working memory only (n = 661). NRG1 has a biological role in brain development and neural function which has been shown to be partially mediated by the NMDA-glutamate pathway, with ErbB4 and AKT1 directly linked to NRG1 downstream. Discussion Findings from this systematic review suggest that the glutamatergic system contributes to the cognitive deficits in schizophrenia, in particular in the areas of memory and working memory. Literature suggests that DTNBP1 and GRM3 are involved in the presynaptic components synthesis and uptake in the glutamatergic pathway, while NRG1 and its downstream signalling are involved in post-synaptic scaffold and signalling. As the difference between memory and working memory appears to be NRG1 and its downstream effects, results indicate presynaptic components synthesis and uptake of glutamate is involved in memory, while post-synaptic scaffold and signalling appears to be involved in working memory. Different parts of the glutamatergic pathway appear to be associated with different cognitive domains, highlighting the importance for cognition to be examined by domain as opposed to globally. By breaking down cognition into multiple domains, it will be easier to identify the molecular mechanisms affecting different cognitive phenotypes in schizophrenia.