Chronic LSD administration produces changes in mPFC gene and protein expression relevant to schizophrenia, as determined by RNA‐Seq and DIGE

Summary

A novel rat model of schizophrenia was developed by treating rats with low doses of LSD for three months. This treatment caused persistent behavioral abnormalities including social deficits, hyperactivity, and anhedonia that continued after the drug was stopped. Protein analysis of the medial prefrontal cortex identified 12 differentially expressed proteins, 9 of which are also dysregulated in post-mortem brain tissue from people with schizophrenia. RNA sequencing showed that chronic LSD alters genes across all major neurotransmitter systems linked to schizophrenia, with many changes involving synaptic plasticity. The findings support chronic LSD treatment as a valid model for studying schizophrenia and may provide insights into the disease's underlying mechanisms.

Study at a glance

Abstract

The objective of this work is to characterize genetic and proteomic changes in a novel rat model of schizophrenia. Three‐month treatment with low doses of the hallucinogenic drug, LSD, induces a range of abnormal behaviors including social deficits, hyperactivity, and anhedonia. These behavioral changes persist in the absence of drug , and likely result from neuroadaptive changes in the medial prefrontal cortex (mPFC), an area of the brain highly implicated in schizophrenia and in the actions of LSD. DIGE proteomic analysis revealed 12 differentially expresed proteins in the mPFC of LSD‐treated rats, 9 of which have previously been identified as dysregulated in schizophrenic post‐mortem cortex. RNA was sequenced using RNA‐Seq, and bioinformatic analysis of the sequence data reveals that chronic LSD induces alterations in genes for each of the major neurotransmitter systems associated with schizophrenia, as well as other genes associated with this disease. Functional clustering of differentially expressed genes reveals subsets involved in synaptic plasticity are highly represented. This data supports the construct validity of chronic LSD as a new model of schizophrenia, and suggests that further investigation of the effects of LSD may reveal important mechanistic insight into the pathophysiology of schizophrenia, and that our model may be used as a discovery platform. Supported by NIH RO1MH092511.