Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jun 8:108:110156. doi: 10.1016/j.pnpbp.2020.110156. Epub 2020 Nov 2.

Abstract

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.

Keywords: Adult hippocampal neurogenesis; C-Fos; Emotional behavior; Lysophosphatidic acid receptor; Working memory; α-CaMKII.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cognition / drug effects
  • Cognition / physiology*
  • Emotions / drug effects
  • Emotions / physiology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Infusions, Intraventricular
  • Isoxazoles / administration & dosage
  • Lysophospholipids / administration & dosage*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Propionates / administration & dosage
  • Receptors, Lysophosphatidic Acid / agonists
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
  • Isoxazoles
  • Lysophospholipids
  • Propionates
  • Receptors, Lysophosphatidic Acid
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, mouse