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. 2012 Jul;22(7):527-35.
doi: 10.1016/j.euroneuro.2011.11.006. Epub 2012 Jan 14.

Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor

Andrea de Bartolomeis  1 , Carmine Tomasetti, Maria Cicale, Pei-Xiong Yuan, Husseini K Manji
Affiliations

Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor

Andrea de Bartolomeis et al. Eur Neuropsychopharmacol. 2012 Jul.

Abstract

Homer proteins are associated with both dopaminergic and glutamatergic function. In addition, these proteins are implicated in many signal transduction pathways that are also putative targets of the mood stabilizers lithium and valproate (VPA). This study investigated the effect of in vivo chronic administration of therapeutically-relevant doses of lithium and VPA on the expression of the inducible (Homer1a and ania-3) and constitutive (Homer1b/c) isoforms of the Homer1 gene in rat brain, and of two other Homer-related genes: Inositol 1,4,5 trisphosphate receptor (IP3R) and Shank. Homer1b/c was significantly decreased in cortex by VPA, and in striatal and accumbal subregions by both lithium and VPA. Both mood stabilizers reduced Homer1b/c expression in the dorsolateral caudate-putamen, while only VPA decreased gene expression in all other striatal subregions. Shank and IP3R were downregulated by both mood stabilizers in the cortex. Neither chronic lithium nor VPA affected Homer immediate-early genes. These results suggest that lithium and VPA similarly modulate the expression of structural postsynaptic genes with topographic specificity in cortical and subcortical regions. Thus, Homer may represent an additional molecular substrate for mood stabilizers, and a potential link with dopaminergic function.

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Conflict of interest statement

Conflict of Interest:

Dr. Manji is a full-time employee of Johnson and Johnson Pharmaceutical Research and Development. Andrea de Bartolomeis has received unrestricted research funding from Astra Zeneca, Janssen-Cilag, and Lundbeck. The funding was made available to the Department of Neuroscience, University of Naples Federico II. He has received honoraria as speaker at educational activity sponsored by Astra-Zeneca Italia, Janssen-Cilag Italy, Eli Lilly, Bristol-Myers Squibb.

All other authors declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Figures

Figure 1
Figure 1
Panel a Diagram of regions of interest (ROIs) quantitated on autoradiographic film images in rat forebrain (section coordinates are approximate from Bregma 1.20 mm to 1.00 mm). 1 = cingulate cortex (Cg); 2 = medial agranular cortex (M2); 3 = motor cortex (M1); 4 = somatosensory cortex (SS); 5 = insular cortex (I); 6 = dorsomedial caudate-putamen (CPDM); 7 = dorsolateral caudate-putamen (CPDL); 8 = ventrolateral caudate-putamen (CPVL); 9 = ventromedial caudate-putamen (CPVM); 10 = core of nucleus accumbens (AcCo); 11 = shell of nucleus accumbens (AcSh). Modified from Paxinos and Watson (1997). Panel b. Illustration of cortico-striatal projections among the ROIs in which gene expression induced by mood stabilizers was measured. PL/IL = prelimbic/infralimbic cortices (not shown).
Figure 2
Figure 2
Panel a autoradiographic film images of Homer 1b/c mRNA detected by means of in situ hybridization histochemistry in coronal brain sections after chronic treatment with control (CTR), lithium (Li), or valproate (VPA). Panel b: Homer 1b/c mRNA levels in subregions of the cortex, caudate-putamen, and nucleus accumbens. Data are reported in relative d.p.m. as mean ± S.E.M. Tukey’s post hoc test: * = vs. CTR (p<0.05)
Figure 3
Figure 3
Panels a and b: Autoradiographic film images of IP3 and Shank mRNA detected by means of in situ hybridization histochemistry in coronal brain sections after acute treatment with control (CTR), lithium (Li), or valproate (VPA). Panels b and c: IP3 and Shank mRNA levels after chronic treatment in the subregions of the cortex, caudate-putamen, and nucleus accumbens. Data are reported in relative d.p.m. as mean ± S.E.M. Tukey’s post hoc test: * = vs. CTR (p<0.05).
See this image and copyright information in PMC

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