Neuronal Heterotopias Affect the Activities of Distant Brain Areas and Lead to Behavioral Deficits.
Neuronal heterotopia refers to brain malformations resulting from deficits of neuronal migration. Individuals with heterotopias show a high incidence of neurological deficits, such as epilepsy. More recently, it has come to be recognized that focal heterotopias may also show a range of psychiatric problems, including cognitive and behavioral impairments. However, because focal heterotopias are not always located in the brain areas responsible for the symptoms, the causal relationship between the symptoms and heterotopias remains elusive. In this study, we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited spatial working memory deficit and low competitive dominance behavior, which have been shown to be closely associated with the activity of the medial prefrontal cortex (mPFC) in rodents. Analysis of the mPFC activity revealed that the immediate-early gene expression was decreased and the local field potentials of the mPFC were altered in the mice with heterotopias compared with the control mice. Moreover, activation of these ectopic and overlying sister neurons using the DREADD (designer receptor exclusively activated by designer drug) system improved the working memory deficits. These findings suggest that cortical regions containing focal heterotopias can affect distant brain regions and give rise to behavioral abnormalities. Significance statement: Recent studies reported that patients with heterotopias have a variety of clinical symptoms, such as cognitive disturbance, psychiatric symptoms, and autistic behavior. However, the causal relationship between the symptoms and heterotopias remains elusive. Here we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited behavioral deficits that have been shown to be associated with the mPFC activity in rodents. The existence of heterotopias indeed altered the neural activities of the mPFC, and direct manipulation of the neural activity of the ectopic neurons and their sister neurons in the overlying cortex improved the behavioral deficit. Thus, our results indicate that focal heterotopias could affect the activities of distant brain areas and cause behavioral abnormalities.
Department of Anatomy, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Kazuhiro
http://orcid.org/0000-0002-3234-1446
K
Ishii
Department of Anatomy, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Ken-ichiro
http://orcid.org/0000-0003-4023-5069
K
Kubo
Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, and Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan.
Toshihiro
T
Endo
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Keitaro
K
Yoshida
Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, and.
Seico
S
Benner
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Yukiko
Y
Ito
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan, Department of Neurobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
Hidenori
http://orcid.org/0000-0002-2896-1298
H
Aizawa
Department of Anatomy, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Michihiko
M
Aramaki
Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan.
Akihiro
http://orcid.org/0000-0001-6099-7306
A
Yamanaka
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan, Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan, and.
Kohichi
K
Tanaka
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Norio
N
Takata
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Kenji F
KF
Tanaka
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Masaru
M
Mimura
Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, and.
Chiharu
C
Tohyama
Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, and Laboratory for Systems Neuroscience and Preventive Medicine, Waseda University Faculty of Human Sciences, Saitama, 359-1192, Japan kazunori@keio.jp kake@waseda.jp.
Masaki
http://orcid.org/0000-0001-9063-9673
M
Kakeyama
Department of Anatomy, Keio University School of Medicine, Tokyo, 160-8582, Japan, kazunori@keio.jp kake@waseda.jp.
Kazunori
K
Nakajima
D000818:Animals; D017781:Genes, Immediate-Early; D054220:Malformations of Cortical Development / Q000503:physiopathology*; D018782:Maze Learning; D008568:Memory; D001523:Mental Disorders / Q000503:physiopathology*; D051379:Mice; D017397:Prefrontal Cortex / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology*; D012919:Social Behavior; D013003:Somatosensory Cortex / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology*
DREADD; IntelliCage; heterotopia; in utero electroporation; neuropsychiatric symptom; optogenetics