Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors

Biol Psychiatry. 2008 Nov 15;64(10):863-70. doi: 10.1016/j.biopsych.2008.06.008. Epub 2008 Jul 17.


Background: Postmortem studies have repeatedly found decreased density and number of glia in cortical regions, including the prefrontal and cingulate areas, from depressed patients. However, it is unclear whether this glial loss plays a direct role in the expression of depressive symptoms.

Methods: To address this question, we characterized the effects of pharmacologic glial ablation in the prefrontal cortex (PFC) of adult rats on behavioral tests known to be affected by stress or antidepressant treatments: sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST), and two-way active avoidance test (AAT). We established the dose and time course for the actions of an astrocyte specific toxin, L-alpha-aminoadipic acid (L-AAA), and compared the behavioral effects of this gliotoxin with the effects of an excitotoxic (ibotenate) lesion and to the effects of chronic stress.

Results: The results demonstrate that L-AAA infusions induced anhedonia in SPT, anxiety in NSFT, and helplessness in FST and AAT. These effects of L-AAA were similar to chronic unpredictable stress (CUS)-induced depressive-like behaviors in these tests. However, ibotenate-induced neurotoxic lesion of the PFC had no effect in these behavioral tests.

Conclusions: The results demonstrate that glial ablation in the PFC is sufficient to induce depressive-like behaviors similar to chronic stress and support the hypothesis that loss of glia contributes to the core symptoms of depression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 2-Aminoadipic Acid / toxicity
  • Analysis of Variance
  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Behavior, Animal
  • Cell Death / drug effects
  • Depression / chemically induced
  • Depression / pathology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / toxicity
  • Exploratory Behavior / drug effects
  • Food Preferences / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Male
  • Maze Learning / drug effects
  • Motor Activity / drug effects
  • Neuroglia / drug effects
  • Neuroglia / pathology*
  • Phosphopyruvate Hydratase / metabolism
  • Prefrontal Cortex / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Excitatory Amino Acid Antagonists
  • Glial Fibrillary Acidic Protein
  • 2-Aminoadipic Acid
  • Phosphopyruvate Hydratase