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

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 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

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

Behavioral effects of CB2-R activation and blockade.

<p><i>A</i>, Mouse spontaneous locomotor activity following acute treatment with CB2 agonist JWH015 (1–20 mg/kg), in mouse strain, C57Bl/6 (a and b); BALBc, (c and d) and DBA/2 (e and f). <i>B</i>, Effect of JWH015 in C57Bl/6 mice in the two compartment black and white box, showing time spent in the black and white chamber. <i>C</i>, Acute effects of SR144528 – a CB2-R antagonist on DBA/2 mouse spontaneous locomotor activity and stereotype behavior. <i>D</i>, Acute effects of SR144528, in DBA/2 male and female mice in the two chamber black and white test box, showing time spent in the black and white chamber.</p

CB2-R gene targeting modifies behavior.

<p><i>A</i>, Behavioral effects of CB2 intracerebral gene targeting by antisense oligonucleotide microinjected into the mouse brain and performance of mice in plus-maze test was assessed before and after 3 days of twice daily microinjection. AS1 and AS2 were before and after CB2 antisense oligo microinjection. V1 and V2 are controls. <i>B</i>, performance in plus-maze test following CMS or mice exposed prenatally to capsaicin and the effect of JWH015 (20 mg/kg).</p

CB2-R- activation and blockade on anhedonia induced by chronic mild stress (CMS).

<p><i>A</i>, Weekly sucrose consumption in stress and control mice. <i>B</i>, Effect of JWH015 (20 mg/kg) on mouse weekly sucrose consumption test. C, Effect of AM630 (1 and 3 mg/kg) on mouse weekly sucrose consumption test.</p

Allelic and genotype distribution of R63Q polymorphism in the <i>CB2 gene</i>.

<p>Comparisons were made between patients with major depression and the healthy controls. Significant differences are observed in allelic frequency and genotype distribution in the R recessive model. OR is odd ratio.</p

Brain CB2-Rs: Immunohistochemistry in mouse and rat brain.

<p><i>A</i>, CB2-IR in apical dendrites and cell bodies of pyramidal neurons of rat cerebral cortex. <i>B</i>, CB2-IR in mouse cerebral cortex. <i>C</i>, CB2-IR in rat corpus callosum and <i>D</i>, CB2-IR in mouse hippocampal allocortex and some interneurons in the striatum oriens and stratum radiatum.</p