Differential DNA-methylation of synaptic genes in CSF and blood in schizophrenia

Abstract The dual-hit model of schizophrenic psychoses suggests that epigenetic alterations may contribute to the disease pathogenesis. Given the significant synaptic loss in patients with schizophrenia (SZ) during puberty, we investigated DNA-methylation patterns of key synaptic target molecules: dopamine transporter (DAT), dopamine receptor D2 (DRD2), microtubule-associated protein tau (MAPT), and postsynaptic density protein 95 (PSD95). Analyses were performed in both blood and cerebrospinal fluid (CSF) samples from patients with SZ (n = 36) and healthy controls (Co) (n = 23). Due to the minimal amount of cell-free DNA available in CSF, different extraction methods were evaluated to achieve the best possible recovery. Ultimately, an adapted ethanol-glycogen precipitation protocol combined with a subsequent bead-based fusion and DNA clean-up was applied. However, despite comparable DNA concentrations obtained from Co and SZ CSF samples, only very few sequences could be obtained from CSF samples of Co, so that results concerning CSF measurements are limited to patients with SZ. In DAT, methylation was significantly higher in the blood of Co compared to both the blood and CSF of patients with SZ. In PSD95, mean methylation levels were higher in the CSF than in the blood of patients with SZ, whereas no difference was detected in the blood between SZ and Co. For MAPT and DRD2, no significant differences in mean methylation rates were observed between groups. Low sequencing success in CSF from Co, despite comparable concentrations to SZ, might point to a higher degree of fragmentation. In SZ, longer DNA fragments may be replenished more frequently. Higher central methylation of PSD95 in patients with SZ, a key regulator of glutamatergic neurotransmission, may reduce gene transcription and thus support the glutamate hypothesis of SZ, which assumes impaired glutamate receptor function. Lower DAT methylation in SZ compared to Co (with similar central and peripheral levels) could indicate a higher availability of the transporter at the synapse in SZ, resulting in a higher clearance of dopamine. This could be a compensatory mechanism concerning the hypothesis of dopaminergic hyperactivity in SZ.