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Altered striatal dopaminergic system in heterozygous Disc1 mutant mice
Author(s) -
Baskaran Rathinasamy,
Lee LiJen
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.447.4
Subject(s) - dopaminergic , dopamine , disc1 , striatum , dopamine transporter , amphetamine , endocrinology , creb , monoaminergic , medicine , tyrosine hydroxylase , dopamine receptor d1 , prepulse inhibition , dopamine receptor , dopamine receptor d2 , biology , receptor , schizophrenia (object oriented programming) , serotonin , biochemistry , gene , psychiatry , transcription factor
Disrupted‐in‐Schizophrenia‐1 ( DISC1 ) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, various Disc1 mutant models were established. We had generated Disc1 mutant mice by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into C57BL/6J strain. In this study, a battery of behavioral tests was conducted to evaluate the behavioral phenotypes and cognitive function in the heterozygous Disc1 mutant (Het) mice. In open field test, novel object recognition test, Y‐maze test, and prepulse inhibition test, no significant differences were observed between wildtype (WT) and Het mice. However, after receiving an intraperitoneal injection of amphetamine (5 mg/kg), greater locomotor activity was noticed in Het mice comparing with WT. Meanwhile, higher amphetamine‐induced c‐fos expression and dopamine level were found in the striatum of Het mice than those in WT mice, suggesting an altered dopaminergic system in the striatum of Het mice. We then quantified the expression of proteins involved in dopaminergic function and DISC1 signaling in the striatum. Tyrosine hydroxylase (TH) level was not changed; dopamine transporter (DAT) and D2 dopamine receptor (D2DR) were increased while D1 dopamine receptor (D1DR) was decreased in Het mice. The expression of glycogen synthase kinase 3 (GSK3α/β) was down regulated in Het mice while some DISC1 interacting proteins such as phosphodiesterase 4B (PDE4B), cAMP response element binding protein (CREB) were not altered. Morphologically, the dendritic complexity and spine density of striatal median spiny neurons were reduced in Het mice. Our results indicated that Disc1 deficit in one allele does not alter the basic behavior and cognitive performance in mice. However, mice lacking one WT Disc1 allele are vulnerable to psychostimulant such as amphetamine, which might be attributed by altered structure and function of striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice which could be a promising animal model of DISC1 haploinsufficiency. Support or Funding Information This work was supported by the Ministry of Science and Technology of the Republic of China; Grant number: 102‐2628‐B‐002‐014‐MY3. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .