Summary: The molecule LRP4 on the surface of astrocytes helps to regulate glutamate levels, a new study reports.
Source: Medical College of Georgia at Augusta University.
A molecule that enables strong communication between our brain and muscles appears to also aid essential communication between our neurons, scientists report.
On the surface of our numerous star-shaped brain cells called astrocytes, they have found the molecule LRP4 is important in ensuring healthy levels of a brain chemical that enables learning and memory, said Dr. Lin Mei, chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University and Georgia Research Alliance Eminent Scholar in Neuroscience.
The brain chemical, or neurotransmitter, is glutamate, the most important excitatory neurotransmitter in the brain, which essentially means it is passed between neurons to help one activate the next. It was known that astrocytes could regulate or modulate brain cell communication by adjusting levels of glutamate.
But now, the MCG scientists have shown that LRP4 is in those astrocytes, and that without it, glutamate release is dramatically reduced. Mice are intellectually impaired and have difficulty with movement, Mei said of the findings he characterizes as “unexpected.” One benefit was protection from seizures because of the reduced excitability of neurons. Removing LRP4 from nearby neurons did not yield the same negative effects.
While much work remains, Mei and his colleagues believe the work published in the journal Nature Neuroscience provides new insight into the critical regulation of neurotransmitters that enable neurons to take action as well as potential therapeutic targets for one day helping individuals with intellectual disabilities.
Once made, glutamate gets passed from one neuron to the next via synapses, much like the arm of one neuron reaching out to hand something to the next. Dysfunction of synapses is associated with a host of neuropsychiatric disorders such as epilepsy, addiction, schizophrenia and autism.
Taking LRP4 out of the equation messes up the delicate balance, the scientists have found. Without it, levels of ATP, a natural energy source for cells that also inhibits glutamate release, also dramatically increase. In fact, regulating ATP levels is one way astrocytes help regulate the level of neurotransmitters, Mei said. But in this scenario, too much ATP translates to too little glutamate. Blocking the receptor ATP eventually activates ameliorates the negative impact that high levels had on the mice.
“When you take LRP4 out of astrocytes, ATP levels released by those astrocytes go super high, which suppresses glutamate transmission,” Mei said.
Astrocytes are the most common of a type of brain cell called glial cells. In fact, astrocytes account for about half of all the cells in the brain, Mei said. While the brain actually has more glial cells than neurons, glial cells were long thought to provide only structural support to the neurons, much like cement supports a house. “That view has been changed and is changing,” said Mei. Now it’s clear that glial cells, like astrocytes, have a role in neurodevelopment and longer-term in regulating communication between two neurons.
In the neuromuscular juncture, Mei’s lab found several years back that LRP4 on the muscle cell surface is a receptor for agrin, a protein that motor neurons release to direct construction of the nerve-muscle juncture. His lab later identified antibodies to LRP4 and agrin as new causes of myasthenia gravis. The new research indicates that release of ATP by astrocytes is also regulated by agrin signaling.
About this neuroscience and learning research article
Funding: The research was funded by the National Institutes of Health and the Department of Veterans Affairs. Postdoctoral fellows Drs. Xiang-Dong Sun and Lei Li are the study’s co-first authors.
Source: Medical College of Georgia at Augusta University Image Source: This NeuroscienceNews.com image is credited to Neurorocker and is licensed CC BY 3.0. Original Research:Abstract for “Lrp4 in astrocytes modulates glutamatergic transmission” by Xiang-Dong Sun, Lei Li, Fang Liu, Zhi-Hui Huang, Jonathan C Bean, Hui-Feng Jiao, Arnab Barik, Seon-Myung Kim, Haitao Wu, Chengyong Shen, Yun Tian, Thiri W Lin, Ryan Bates, Anupama Sathyamurthy, Yong-Jun Chen, Dong-Min Yin, Lei Xiong, Hui-Ping Lin, Jin-Xia Hu, Bao-Ming Li, Tian-Ming Gao, Wen-Cheng Xiong and Lin Mei in Nature Neuroscience. Published online June 13 2016 doi:10.1038/nn.4326
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Medical College of Georgia at Augusta University. “How Astrocytes Help Us Learn.” NeuroscienceNews. NeuroscienceNews, 23 June 2016. <https://neurosciencenews.com/neuroscience-astrocytes-learning-4546/>.[/cbtab][cbtab title=”APA”]Medical College of Georgia at Augusta University. (2016, June 23). How Astrocytes Help Us Learn. NeuroscienceNews. Retrieved June 23, 2016 from https://neurosciencenews.com/neuroscience-astrocytes-learning-4546/[/cbtab][cbtab title=”Chicago”]Medical College of Georgia at Augusta University. “How Astrocytes Help Us Learn.” https://neurosciencenews.com/neuroscience-astrocytes-learning-4546/ (accessed June 23, 2016).[/cbtab][/cbtabs]
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.
“Lrp4 in astrocytes modulates glutamatergic transmission” by Xiang-Dong Sun, Lei Li, Fang Liu, Zhi-Hui Huang, Jonathan C Bean, Hui-Feng Jiao, Arnab Barik, Seon-Myung Kim, Haitao Wu, Chengyong Shen, Yun Tian, Thiri W Lin, Ryan Bates, Anupama Sathyamurthy, Yong-Jun Chen, Dong-Min Yin, Lei Xiong, Hui-Ping Lin, Jin-Xia Hu, Bao-Ming Li, Tian-Ming Gao, Wen-Cheng Xiong and Lin Mei in Nature Neuroscience. Published online June 13 2016 doi:10.1038/nn.4326