The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice

Cecilia Csölle, Rómeó D. Andó, A. Kittel, Flóra Gölöncsér, M. Baranyi, Krisztina Soproni, D. Zelena, J. Haller, Tamás Németh, A. Mócsai, B. Sperlágh

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Abstract

The purpose of this study was to explore how genetic deletion and pharmacological antagonism of the P2X7 receptor (P2rx7) alter mood-related behaviour, gene expression and stress reactivity in the brain. The forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperlocomotion (AH) tests were used in wild-type (P2rx7 +/+) and P2rx7-deficient (P2rx7 -/-) mice. Biogenic amine levels were analysed in the amygdala and striatum, adrenocorticotropic hormone (ACTH) and corticosterone levels were measured in the plasma and pituitary after restraint stress. Chimeric mice were generated by bone marrow transplantation. A whole genome microarray analysis with real-time polymerase chain reaction validation was performed on the amygdala. In the absence of P2rx7s decreased behavioural despair in the FST, reduced immobility in the TST and attenuated amphetamine-induced hyperactivity were detected. Basal norepinephrine levels were elevated in the amygdala, whereas stress-induced ACTH and corticosterone responses were alleviated in P2rx7 -/- mice. Sub-acute treatment with the selective P2rx7 antagonist, Brilliant Blue G, reproduced the effect of genetic deletion in the TST and AH test in P2rx7 +/+ but not P2rx7 -/- mice. No change in behavioural phenotype was observed in chimeras lacking the P2rx7 in their haematopoietic compartment. Whole genome microarray analysis indicated a widespread up-and down-regulation of genes crucial for synaptic function and neuroplasticity by genetic deletion. Here, we present evidence that the absence of P2rx7s on non-haematopoietic cells leads to a mood-stabilizing phenotype in several behavioural models and suggest a therapeutic potential of P2rx7 antagonists for the treatment of mood disorders.

Original languageEnglish
Pages (from-to)213-233
Number of pages21
JournalInternational Journal of Neuropsychopharmacology
Volume16
Issue number1
DOIs
Publication statusPublished - Feb 2013

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Purinergic P2X7 Receptors
Hindlimb Suspension
Amphetamine
Amygdala
Gene Expression
Microarray Analysis
Corticosterone
Adrenocorticotropic Hormone
Genome
Phenotype
Neuronal Plasticity
Biogenic Amines
Bone Marrow Transplantation
Mood Disorders
Real-Time Polymerase Chain Reaction
Norepinephrine
Up-Regulation
Therapeutics
Down-Regulation
Pharmacology

Keywords

  • Antagonists
  • bipolar disorder
  • depression
  • knockout
  • microarray
  • P2X7 receptor

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

Cite this

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title = "The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice",
abstract = "The purpose of this study was to explore how genetic deletion and pharmacological antagonism of the P2X7 receptor (P2rx7) alter mood-related behaviour, gene expression and stress reactivity in the brain. The forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperlocomotion (AH) tests were used in wild-type (P2rx7 +/+) and P2rx7-deficient (P2rx7 -/-) mice. Biogenic amine levels were analysed in the amygdala and striatum, adrenocorticotropic hormone (ACTH) and corticosterone levels were measured in the plasma and pituitary after restraint stress. Chimeric mice were generated by bone marrow transplantation. A whole genome microarray analysis with real-time polymerase chain reaction validation was performed on the amygdala. In the absence of P2rx7s decreased behavioural despair in the FST, reduced immobility in the TST and attenuated amphetamine-induced hyperactivity were detected. Basal norepinephrine levels were elevated in the amygdala, whereas stress-induced ACTH and corticosterone responses were alleviated in P2rx7 -/- mice. Sub-acute treatment with the selective P2rx7 antagonist, Brilliant Blue G, reproduced the effect of genetic deletion in the TST and AH test in P2rx7 +/+ but not P2rx7 -/- mice. No change in behavioural phenotype was observed in chimeras lacking the P2rx7 in their haematopoietic compartment. Whole genome microarray analysis indicated a widespread up-and down-regulation of genes crucial for synaptic function and neuroplasticity by genetic deletion. Here, we present evidence that the absence of P2rx7s on non-haematopoietic cells leads to a mood-stabilizing phenotype in several behavioural models and suggest a therapeutic potential of P2rx7 antagonists for the treatment of mood disorders.",
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author = "Cecilia Cs{\"o}lle and And{\'o}, {R{\'o}me{\'o} D.} and A. Kittel and Fl{\'o}ra G{\"o}l{\"o}ncs{\'e}r and M. Baranyi and Krisztina Soproni and D. Zelena and J. Haller and Tam{\'a}s N{\'e}meth and A. M{\'o}csai and B. Sperl{\'a}gh",
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T1 - The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice

AU - Csölle, Cecilia

AU - Andó, Rómeó D.

AU - Kittel, A.

AU - Gölöncsér, Flóra

AU - Baranyi, M.

AU - Soproni, Krisztina

AU - Zelena, D.

AU - Haller, J.

AU - Németh, Tamás

AU - Mócsai, A.

AU - Sperlágh, B.

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