Journal Article

Enriched Environment Reverts Somatostatin Interneuron Loss in MK-801 Model of Schizophrenia

Harkaitz, Bengoetxea, Murueta-Goyena Ane, Lafuente, José Vicente, Ortuzar Naiara

2020

Overview

Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5 mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor—tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups. We observed that early-life MK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-life NMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implications for schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.

• Publisher: Springer Nature B.V
• Subject: AKT protein / Anatomy / Brain architecture / Brain-derived neurotrophic factor / Dizocilpine / Enrichment / Extracellular signal-regulated kinase / Glutamic acid receptors (ionotropic) / Hippocampus / Interneurons / Kinases / Mental disorders / N-Methyl-D-aspartic acid receptors / Prefrontal cortex / Protein-tyrosine kinase / Schizophrenia / Signal transduction / Somatostatin / TrkB receptors