TY - JOUR
T1 - Reelin Supplementation Into the Hippocampus Rescues Abnormal Behavior in a Mouse Model of Neurodevelopmental Disorders
AU - Ibi, Daisuke
AU - Nakasai, Genki
AU - Koide, Nayu
AU - Sawahata, Masahito
AU - Kohno, Takao
AU - Takaba, Rika
AU - Nagai, Taku
AU - Hattori, Mitsuharu
AU - Nabeshima, Toshitaka
AU - Yamada, Kiyofumi
AU - Hiramatsu, Masayuki
N1 - Funding Information:
The authors would like to thank the Division for Research of Laboratory Animals of Meijo University for their technical assistance. Funding. This research was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; the Japan Agency for Medical Research and Development (AMED) under grant no. JP20dm0107087; the Scientific Research on Innovative Areas “Glial assembly: a new regulatory machinery of brain function and disorders” program; the Scientific Research on Innovative Areas “Comprehensive Brain Science Network” program; and the Uehara Memorial Foundation (to DI and KY), the SENSHIN Medical Research Foundation, YOKOYAMA Foundation for Clinical Pharmacology (YRY-1909), The Pharmacological Research Foundation, Tokyo, The Research Foundation for Pharmaceutical Sciences, the Smoking Research Foundation, the Takeda Science Foundation (to DI), and the Research Center for Pathogenesis of Intractable Disease from the Research Institute of Meijo University (to DI and MHi). The Japan Society for the Promotion of Science 17H04252 (to ToN), 15H06719 and 16K19786 (to DI), and 17H04031 and 20H03428 (to KY) were also used to fund this study. The Matching Fund Subsidy for Private Universities and the Private University Research Branding Project of the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) purchased the confocal laser scanning fluorescence microscopy used in this study.
Publisher Copyright:
© Copyright © 2020 Ibi, Nakasai, Koide, Sawahata, Kohno, Takaba, Nagai, Hattori, Nabeshima, Yamada and Hiramatsu.
PY - 2020/9/2
Y1 - 2020/9/2
N2 - In the majority of schizophrenia patients, chronic atypical antipsychotic administration produces a significant reduction in or even complete remission of psychotic symptoms such as hallucinations and delusions. However, these drugs are not effective in improving cognitive and emotional deficits in patients with schizophrenia. Atypical antipsychotic drugs have a high affinity for the dopamine D2 receptor, and a modest affinity for the serotonin 5-HT2A receptor. The cognitive and emotional deficits in schizophrenia are thought to involve neural networks beyond the classical dopaminergic mesolimbic pathway, however, including serotonergic systems. For example, mutations in the RELN gene, which encodes Reelin, an extracellular matrix protein involved in neural development and synaptic plasticity, are associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Furthermore, hippocampal Reelin levels are down-regulated in the brains of both schizophrenic patients and in rodent models of schizophrenia. In the present study, we investigated the effect of Reelin microinjection into the mouse hippocampus on behavioral phenotypes to evaluate the role of Reelin in neurodevelopmental disorders and to test a therapeutic approach that extends beyond classical monoamine targets. To model the cognitive and emotional deficits, as well as histological decreases in Reelin-positive cell numbers and hippocampal synaptoporin distribution, a synaptic vesicle protein, offspring that were prenatally exposed to maternal immune activation were used. Microinjections of recombinant Reelin protein into the hippocampus rescued impairments in object memory and anxiety-like behavior and recruited synaptoporin in the hippocampus in offspring exposed to antenatal inflammation. These results suggest that Reelin supplementation has the potential to treat cognitive and emotional impairments, as well as synaptic disturbances, in patients with neurodevelopmental disorders such as schizophrenia.
AB - In the majority of schizophrenia patients, chronic atypical antipsychotic administration produces a significant reduction in or even complete remission of psychotic symptoms such as hallucinations and delusions. However, these drugs are not effective in improving cognitive and emotional deficits in patients with schizophrenia. Atypical antipsychotic drugs have a high affinity for the dopamine D2 receptor, and a modest affinity for the serotonin 5-HT2A receptor. The cognitive and emotional deficits in schizophrenia are thought to involve neural networks beyond the classical dopaminergic mesolimbic pathway, however, including serotonergic systems. For example, mutations in the RELN gene, which encodes Reelin, an extracellular matrix protein involved in neural development and synaptic plasticity, are associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Furthermore, hippocampal Reelin levels are down-regulated in the brains of both schizophrenic patients and in rodent models of schizophrenia. In the present study, we investigated the effect of Reelin microinjection into the mouse hippocampus on behavioral phenotypes to evaluate the role of Reelin in neurodevelopmental disorders and to test a therapeutic approach that extends beyond classical monoamine targets. To model the cognitive and emotional deficits, as well as histological decreases in Reelin-positive cell numbers and hippocampal synaptoporin distribution, a synaptic vesicle protein, offspring that were prenatally exposed to maternal immune activation were used. Microinjections of recombinant Reelin protein into the hippocampus rescued impairments in object memory and anxiety-like behavior and recruited synaptoporin in the hippocampus in offspring exposed to antenatal inflammation. These results suggest that Reelin supplementation has the potential to treat cognitive and emotional impairments, as well as synaptic disturbances, in patients with neurodevelopmental disorders such as schizophrenia.
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U2 - 10.3389/fncel.2020.00285
DO - 10.3389/fncel.2020.00285
M3 - Article
AN - SCOPUS:85091000316
VL - 14
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 285
ER -