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

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.