The Role of Pdxdc1 in Modulating Prepulse Inhibition of the Acoustic Startle Reflex in Mice

Prepulse inhibition of the acoustic startle reflex (PPI) is a common measure of sensorimotor gating that is abnormal in many neuropsychiatric diseases including schizophrenia. Current treatments for schizophrenia share a common mechanism of blocking the dopamine D2 receptor. However, existing antipsychotic medications are ineffective for many patients and cause severe side effects. Better medications are needed, and identifying new potential treatment targets is the first step in improving outcomes for this debilitating illness. Deficits in PPI can be improved by existing antipsychotic medications used to treat schizophrenia. I sought to identify novel molecular modulators of PPI, reasoning that these could be new treatment targets for schizophrenia. To accomplish this, brain mRNA transcript levels were correlated with PPI in six different strains of inbred mice with a range of PPI levels. Although many brain areas are involved in PPI, the hippocampus, striatum and brainstem were the three areas examined. Affymetrix MOE 420 microarrays were used to measure mRNA transcript levels and transcripts that best correlated with PPI were selected for verification using real-time RT-PCR. Pyridoxal-dependent decarboxylase domain containing 1 (Pdxdc1) encodes a 787aa putative pyridoxal-dependent decarboxylase, and was selected for further study because of a strong negative correlation of transcript abundance with PPI. I measured the distribution of Pdxdc1 mRNA and protein expression in mouse brain using in situ hybridization and immunohistochemistry, respectively, and found relatively strong expression levels of both molecules in the hippocampus. The functional role of Pdxdc1 in modulating PPI was verified by knocking down protein in the mouse hippocampus in vivo. Stereotactic injection of lentivirus containing a plasmid coding for anti-Pdxdc1 shRNA into the dentate gyrus of the hippocampus significantly increased PPI in male C57BL/6J mice. shRNA-mediated interference reduced Pdxdc1 protein levels by 30% and increased PPI by approximately 15%, without substantially altering spatial learning and memory-related behaviours, but with some effect on spontaneous locomotor activity. This suggests that Pdxdc1 may modulate PPI and warrants further study as a potential target for drug development.Ph.D