Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions. 1 Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity. 2-7 Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence. [8][9][10][11] We performed an association study between the ser310ala GRIK3 polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia. Molecular Psychiatry (2002) 7, 416-418. DOI: 10.1038/ sj/mp/4000987Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucinations and delusions. Family, twin and adoption studies strongly evidenced genetic susceptibility and a pattern of inheritance belonging to the class of multifactorial complex disorders. 1 Many hypotheses have been made to explain the pathophysiology of schizophrenia and several studies suggest that dysfunctions in metabolism of neurotransmitters, such as dopamine, serotonin and glutamate, are directly implicated in the pathogenesis of this severe illness. A growing number of studies focused the attention on dysfunctions in glutamatergic pathway as a major susceptibility factor for schizophrenia. 2 Glutamate receptors are widely expressed in the central nervous system and play a fundamental role in synaptic plasticity and in all the processes underlying learning and memory. In particular the calcium influx through ionotropic glutamate receptors influences the regulation of transcriptional, translational and posttranslational processes fundamental for the function of brain cells. 3 One of the hypotheses about the molecular mechanisms leading to schizophrenia is the presence of an excessive activation of glutamate receptors. An increase in the basic metabolic activity along the glutamatergic axons has been demonstrated by PET scan studies in the cingulate cortex and hippocampal region of schizophrenic patients. 4,5 It has been hypothesised that this may cause a progressive excitotoxic cell death through the disruption of ionic gradients and the increase of intracellular calcium concentration. 6,7 Numerous findings suggested that ionotropic receptors of the kainate subtype, composed by the low affinity subunits GRIK1, GRIK2, GRIK3, and the high af...