Hippocampal small RNAs from patients with schizophrenia induce specific cognitive and neural phenotypes in mice

Schizophrenia is a neuropsychiatric syndrome characterized by the presence of psychotic, negative and cognitive symptoms. Cognitive deficits can appear even before the onset of the first psychotic episode and their severity has been recently associated with altered levels of small RNAs (sRNAs), including microRNAs. Nevertheless, how the dysregulation of sRNAs can lead to cognitive impairments and their role in the onset and pathophysiology of the disorder are still unknown. In our research, we hypothesized that hippocampal sRNAs generated in patients with schizophrenia could contribute to the impairment of specific cognitive domains that are altered in the disease. Through deep sequencing, we identified novel dysregulated sRNAs (including microRNAs and tRNA-derived fragments) in the hippocampus of patients with schizophrenia. Furthermore, when injected in the hippocampus of wild-type mice, animals exhibited an impairment in spatial short-term memory accompanied by a reduction in spine density of CA1 pyramidal neurons. RNA-sequencing of the hippocampus of injected mice revealed changes in key pathways related to neurotransmission. Specifically, we found higher levels of the presynaptic marker for Parvalbumin interneurons synaptotagmin II (Syt2), mirroring observations made in the brain of schizophrenia patients. We also detected subtle morphological changes in mouse hippocampal microglia in response to sRNAs from affected individuals. Our results point out that sRNAs can contribute to cognitive symptoms in schizophrenia through synaptic alterations, highlighting these molecules as promising novel therapeutic targets for the disorder.