Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Anastasia M. Sorokina, Michael Saul, Tassia M. Goncalves, Joseph V. Gogola, Petra Majdak, Sandra L. Rodriguez-Zas, Justin S. Rhodes

Research output: Contribution to journalArticle

Abstract

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHDlike symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.

Original languageEnglish (US)
Article numbere0201553
JournalPloS one
Volume13
Issue number8
DOIs
StatePublished - Aug 2018

Fingerprint

Corpus Striatum
Attention Deficit Disorder with Hyperactivity
Transcriptome
transcriptome
Genes
animal models
mice
Synaptophysin
Physiology
Amphetamine
synapse
amphetamine
Synapses
Actin Depolymerizing Factors
Down-Regulation
Amphetamines
genes
amphetamines
Fibronectins
physiology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling. / Sorokina, Anastasia M.; Saul, Michael; Goncalves, Tassia M.; Gogola, Joseph V.; Majdak, Petra; Rodriguez-Zas, Sandra L.; Rhodes, Justin S.

In: PloS one, Vol. 13, No. 8, e0201553, 08.2018.

Research output: Contribution to journalArticle

Sorokina, Anastasia M. ; Saul, Michael ; Goncalves, Tassia M. ; Gogola, Joseph V. ; Majdak, Petra ; Rodriguez-Zas, Sandra L. ; Rhodes, Justin S. / Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling. In: PloS one. 2018 ; Vol. 13, No. 8.
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abstract = "Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHDlike symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46{\%} reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.",
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