Molecular effects of lithium are partially mimicked by inositol-monophosphatase (IMPA)1 knockout mice in a brain region-dependent manner

• Published in: European neuropsychopharmacology 2015-03, Vol.25 (3), p.425-434
• Main Authors: Damri, O, Sade, Y, Toker, L, Bersudsky, Y, Belmaker, R.H, Agam, G, A.N., Azab
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - pharmacology; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Brain - anatomy & histology; Brain - drug effects; Brain - metabolism; Cytokines - metabolism; Cytokines levels; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Inositol monophosphatase1; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Knockout mice; Lithium; Lithium - pharmacology; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Myristoylated Alanine-Rich C Kinase Substrate; Peroxiredoxins - genetics; Peroxiredoxins - metabolism; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Psychiatry; RNA, Messenger - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2014.06.012

Abstract We have previously shown that homozygote knockout (KO) of inositol-monophosphatase1 ( IMPA1 ) results in lithium (Li)-like behavior. We now aimed to find out whether Li-treated mice and IMPA1 KO mice exhibit neurochemical similarity at the gene- and protein-expression level. Hippocampal and frontal cortex B-cell lymphoma ( Bcl-2 ), Bcl-2-associated X protein ( BAX ), P53 , Perodoxin2 ( PRDX2 ), myristoylated alanine-rich C kinase substrate ( MARCKS ) and neuropeptide Y ( NPY ) mRNA levels, and hippocampal, frontal cortex and hypothalamic cytokine levels, all previously reported to be affected by lithium treatment, were measured in three groups of mice: wildtype (WT) on regular-food (RF), WT on Li-supplemented food (Li-treated) and IMPA1 -KOs. Hippocampal and frontal cortex Bcl-2 and MARCKS were the only genes commonly affected (downregulated) by Li and IMPA1 KO; Bcl-2 - by 28% and 19%, respectively; MARCKS – by about 20% in both regions. The effect of Li and of IMPA1 KO on cytokine levels differed among the three brain areas studied. Only in the hippocampus both interventions exerted similar effects. Frontal cortex cytokine levels were unaffected neither by Li nor by IMPA1 KO. Similar changes in Bcl-2 and MARCKS but not in PRDX2 and NPY following both Li-treatment and IMPA1 KO suggest a mechanism different than inositol-monophosphatase1 inhibition for Li׳s effect on the latter genes. The cytokine levels results suggest that the mechanism mediating Li׳s effect on the inflammatory system differs among brain regions. Only in the hippocampus the results favor the involvement of the phosphatidylinositol (PI) cycle.