TY - JOUR
T1 - Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks
AU - Asada-Utsugi, M.
AU - Uemura, K.
AU - Kubota, M.
AU - Noda, Y.
AU - Tashiro, Y.
AU - Uemura, T. M.
AU - Yamakado, H.
AU - Urushitani, M.
AU - Takahashi, R.
AU - Hattori, S.
AU - Miyakawa, T.
AU - Ageta-Ishihara, N.
AU - Kobayashi, K.
AU - Kinoshita, M.
AU - Kinoshita, A.
N1 - Funding Information:
AK was supported by Health Labour Sciences Research Grant from the Ministry of Health Labour and Welfare (H17-Choju-005) and Grant-in-Aid for Scientific Research(B) (20300124) from Ministry of Education, Culture, Sports, Science and Technology in Japan. This study is partly supported by "Joint Usage/Research Center for Genes, Brain and Behavior “accredited by Minister of Education, Culture, Sports, Science and Technology in Japan (for authors of Fujita Medical School).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.
AB - N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.
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U2 - 10.1186/s13041-021-00738-1
DO - 10.1186/s13041-021-00738-1
M3 - Article
C2 - 33494786
AN - SCOPUS:85099857275
VL - 14
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 23
ER -