Experimental Evidence for the Involvement of PDLIM5 in Mood Disorders in Hetero Knockout Mice

<div><p>Background</p><p>Reports indicate that PDLIM5 is involved in mood disorders. The <i>PDLIM5</i> (PDZ and LIM domain 5) gene has been genetically associated with mood disorders; it’s expression is upregulated in the postmortem brains of patients with bipolar disorder and downregulated in the peripheral lymphocytes of patients with major depression. Acute and chronic methamphetamine (METH) administration may model mania and the evolution of mania into psychotic mania or schizophrenia-like behavioral changes, respectively.</p> <p>Methods</p><p>To address whether the downregulation of PDLIM5 protects against manic symptoms and cause susceptibility to depressive symptoms, we evaluated the effects of reduced <i>Pdlim5</i> levels on acute and chronic METH-induced locomotor hyperactivity, prepulse inhibition, and forced swimming by using <i>Pdlim5</i> hetero knockout (KO) mice.</p> <p>Results</p><p>The homozygous KO of <i>Pdlim5</i> is embryonic lethal. The effects of METH administration on locomotor hyperactivity and the impairment of prepulse inhibition were lower in <i>Pdlim5</i> hetero KO mice than in wild-type mice. The transient inhibition of PDLIM5 (achieved by blocking the translocation of protein kinase C epsilon before the METH challenge) had a similar effect on behavior. <i>Pdlim5</i> hetero KO mice showed increased immobility time in the forced swimming test, which was diminished after the chronic administration of imipramine. Chronic METH treatment increased, whereas chronic haloperidol treatment decreased, <i>Pdlim5</i> mRNA levels in the prefrontal cortex. Imipramine increased <i>Pdlim5</i> mRNA levels in the hippocampus.</p> <p>Conclusion</p><p>These findings are partially compatible with reported observations in humans, indicating that PDLIM5 is involved in psychiatric disorders, including mood disorders.</p> </div

Effect of METH administration on locomotor activity and prepulse inhibition.

<p>Relative locomotor activity and prepulse inhibition after acute (A, B, C) and chronic (D, E, F) administration of METH in <i>Pdlim5</i>+/+ and <i>Pdlim5</i>+/− mice. Values are shown as mean ± SD. * <i>p</i><0.05 and ** <i>p</i><0.01 by ANOVA.</p

Effects of PKCε-TIP on locomotor activity and prepulse inhibition response to METH.

<p>Relative locomotor activity (A, B) and prepulse inhibition (C) by the treatment of PKCε-TIP after chronic METH administration. Values are shown as mean ± SD. P values are based on ANOVA. * p<0.05 and ** p<0.01 by ANOVA.</p

Relative Pdlim5 expression levels after METH, haloperidol and imipramine administrations in mice brains.

<p>Seven-week-old C57BL/6J male mice were treated with an intraperitoneal injection (i.p.) of METH (3.0 mg/kg, once daily for 14 days) (A, B), haloperidol (1 mg/kg, once daily for 49 days) (C), imipramine (20 mg/kg, once daily for 14 days) (D), or vehicle-saline. The upregulated <i>Pdlim5</i> expression in the prefrontal cortex of chronic METH-administered mice (A) was confirmed by a separate experiment using a different mice cohort (B). Values are shown as mean ± SD. * <i>p</i><0.05 and ** <i>p</i><0.01 by Student’s t test.</p

Effect of imipramine treatment on forced swimming.

<p>Immobility time of <i>Pdlim5</i> hetero KO and wild-type mice in the forced swimming test with saline or chronic imipramine administration. Values are shown as mean ± SD. * p<0.05 and ** p<0.01 by ANOVA.</p