Huimeng Lei, PhD; Juan Lai, MS; Xiaohong Sun, BS; Qunyuan Xu, MD, PhD; Guoping Feng, MD, PhD
Background: Obsessive–compulsive disorder (OCD) is a common psychiatric disorder that affects about 2% of the population, but the underlying neuropathophysiology of OCD is not well understood. Although increasing lines of evidence implicate dysfunction of the orbitofrontal cortex (OFC) in OCD, a detailed understanding of the functional alterations in different neuronal types in the OFC is still elusive.
Methods: We investigated detailed activity pattern changes in putative pyramidal neurons and interneurons, as well as local field potential oscillations, in the lateral OFC underlying OCD-relevant phenotypes. We applied in vivo multichannel recording in an awake OCD mouse model that carried a deletion of the Sapap3 gene, and in wild type littermates.
Results: Compared with wild type mice, the lateral OFC of Sapap3 knockout mice exhibited network dysfunction, demonstrated by decreased power of local field potential oscillations. The activity of inhibitory and excitatory neurons in the lateral OFC showed distinct perturbations in Sapap3 knockout mice: putative interneurons exhibited increased activity; putative pyramidal neurons exhibited enhanced bursting activity; and both putative pyramidal neurons and interneurons exhibited enhanced discharge variability and altered synchronization.
Limitations: To exclude motor activity confounders, this study examined functional alterations in lateral OFC neurons only when the mice were stationary.
Conclusion: We provide, to our knowledge, the first direct in vivo electrophysiological evidence of detailed functional alterations in different neuronal types in the lateral OFC of an OCD mouse model. These findings may help in understanding the underlying neuropathophysiology and circuitry mechanisms for phenotypes relevant to OCD, and may help generate and refine hypotheses about potential biomarkers for further investigation.
Submitted Feb. 28, 2018; Revised May 18, 2018; Accepted Jun. 27, 2018; Published online Nov. 7, 2018
Acknowledgements: We thank Dr. Kathleen B. Quast for her comments on the manuscript. This work was supported by grants from the National Natural Science Foundation of China (grant no. 31371108, 31171051), the Natural Science Foundation of Beijing (grant no. 5132007, 5112008), the General Program of Science and Technology Development Project of Beijing Municipal Education Commission of China (grant no. KM201110025001), the Beijing Municipal Technology Foundation for Selected Overseas Chinese Scholars, the Simons Initiative on Autism and the Brain Infrastructure Grant Program.
Affiliations: From the Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Centre of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing, China (Lei, Lai, Sun, Xu); the McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (Feng); and the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts (Feng).
Competing interests: None declared.
Contributors: H. Lei, Q. Xu and G. Feng designed the study. H. Lei, J. Lai and X. Sun acquired the data, which H. Lei and J. Lai analyzed. H. Lei and G. Feng wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial
contributions to the paper.
Correspondence to: H. Lei, Department of Neurobiology, Capital Medical University, You An Men Wai, Xi Tou Tiao, No. 10 Beijing, Beijing 1000069, China; email@example.com; G. Feng, McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; firstname.lastname@example.org.