Schizophrenia is a neuropsychiatric syndrome that affects around 1% of the world population. It is characterized by psychotic or positive symptoms, negative symptoms and cognitive deficits. Currently, antipsychotic treatments can help to manage psychotic symptoms in acute episodes of schizophrenia. However, there is an unmet medical need for the treatment of those cognitive symptoms that appear since the premorbid phase and affect almost 98% of patients. Despite the identification of some molecular pathways that are impaired in schizophrenia, little is known about the possible contribution that small non-coding RNAs (sRNAs) may have in its aetiology and pathophysiology.To define the contribution of sRNAs to the cognitive symptoms of schizophrenia, we have developed a novel translational model based on the injection of sRNAs from the brain of schizophrenic patients or non-affected individuals into the brain of wild-type mice.Wild-type mice receiving sRNAs from schizophrenic patients showed an impairment in spatial working memory measured by the T-maze test, in comparison with mice receiving control sRNAs. Golgi staining revealed that sRNAs from schizophrenic patients induced a decrease in the spine density of the pyramidal neurons from the CA1 hippocampal region in mice. RNA-seq data showed an altered hippocampal expression of synaptic genes related to dendritic spine development and function. Characterization of sRNA profiles by sequencing of patients’ samples will allow us to define potential candidates responsible for these effects.In summary, our results suggest that sRNAs might be sufficient for inducing cognitive symptoms and could play a role as important contributors in schizophrenia.