Enriched Environment Reverts Somatostatin Interneuron Loss in MK-801 Model of Schizophrenia
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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.
KeywordsNMDAR BDNF-TrkB Medial prefrontal cortex Hippocampus
JV Lafuente has been a recipient of the IKERMUGIKORTASUNA program (MV 2018-1-33, Basque Government), and he thanks Dr. William Jr. Slikker and Dr. Sherry Ferguson (NCTR, Jefferson AK) for their valuable contribution to the development of this manuscript.
This work has been partially supported by the University of the Basque Country UPV/EHU (EHU 14/33, PPG 17/51) and by the Basque Government (GIC IT 901/16).
Compliance with Ethical Standards
All procedures were performed in accordance with the European Recommendations 2007/526/EC and were approved by the Ethical Committee on Animal Welfare of the University of the Basque Country (UPV/EHU).
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