Lrp4 in astrocytes modulates glutamatergic transmission.
Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP, whose level was elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice were impaired in locomotor activity and spatial memory and were resistant to seizure induction. These impairments could be ameliorated by blocking the adenosine A1 receptor. The results reveal a critical role for Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity.
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Xiang-Dong
XD
Sun
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Lei
L
Li
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Fang
F
Liu
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Zhi-Hui
ZH
Huang
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Jonathan C
JC
Bean
Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, China.
Hui-Feng
HF
Jiao
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Arnab
A
Barik
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Seon-Myung
SM
Kim
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Haitao
0000-0001-8437-3194
H
Wu
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Chengyong
C
Shen
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Yun
Y
Tian
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Thiri W
TW
Lin
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Ryan
R
Bates
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Anupama
0000-0001-9731-3043
A
Sathyamurthy
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Yong-Jun
YJ
Chen
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Dong-Min
0000-0001-9329-050X
DM
Yin
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Lei
L
Xiong
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Hui-Ping
HP
Lin
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.
Jin-Xia
JX
Hu
Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, China.|Jiangxi Medical School, Nanchang University, Nanchang, China.
Bao-Ming
BM
Li
State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, Southern Medical University, Guangzhou, China.
Tian-Ming
TM
Gao
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.|Charlie Norwood Virginia Medical Center, Augusta, Georgia, USA.
Wen-Cheng
WC
Xiong
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.|Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, China.|Jiangxi Medical School, Nanchang University, Nanchang, China.|Charlie Norwood Virginia Medical Center, Augusta, Georgia, USA.
Lin
L
Mei
D000255:Adenosine Triphosphate / Q000378:metabolism; D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D018171:Agrin; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D011950:Receptors, Cholinergic; D011973:Receptors, LDL; D000255:Adenosine Triphosphate