The Wronged Neural Signal Receptor
As we all know, our nervous system consists of thousands of millions of nerve cells (aka neurons), which are the smallest units in the system that can generate and transport neural signals. These neurons can not only do their jobs by themselves, but also join together to form a gigantic network that becomes the basis of our cognitive activities. How do neurons connect with each other? Neuroscientists have found that there exist specialized junctions between neurons, termed, which seem to be some extremely tiny gaps. These gaps are not really “gaps”. Actually, neural signals can pass through these gaps from one neuron to the next without any difficulty. “How amazing!” as you might think, these magic “gaps” mainly rely on two kinds of small molecules, neurotransmitters and receptors, to fulfill their responsibilities.
Today, our main role in this article is a type of neurotransmitter receptor called. Its name comes from an artificial chemical called that can activate it. In the nervous system, AMPA receptor’s native corresponding neurotransmitter (the molecule released by pre-synaptic neuron that can bind to and activate it) is glutamate. Once glutamate binds AMPA receptor, the structure of AMPA receptor will change to become an opening channel for positive valent ions, such as sodium and potassium, thus changing the membrane electrical property of the post-synaptic neuron in order to generate new neural signal for further transmission. AMPA receptor is composed of several small molecules and its composition is very critical for its functions. One of these small molecules is called , which can determine the types of ions that can pass through AMPA receptor. Generally speaking, GluA2-containing AMPA receptor can work together with another type of glutamate receptor, called , to initiate , which is a very important underlying mechanism for learning and memory.
As we can see, GluA2-containing AMPA receptors serve essential roles in our nervous system. However, under a disease condition called, the body’s immune system would wrongly attack this kind of receptors. In this new paper published in Neuron magazine by , researchers sought to reveal how these wronged neural signal receptors would interfere with normal functions of our nervous system.
Autoimmune encephalitis is a kind of disorder in which antibodies against certain protein molecules in the nervous system are produced by unknown reasons.are immune molecules produced by immune cells that can bind their target proteins and cause conformational change of those proteins. Usually, antibodies will only target bacterial or viral proteins that are not originated in our body. However, in autoimmune encephalitis, antibodies against important molecules in the brain are massively produced, which will severely impede the brain’s functions and cause symptoms like memory loss, anxiety and seizure.
To investigate how these antibodies trigger disease, in today’s paper Haselmann et al. focused on antibodies against GluA2-containing AMPA receptors which can be found in some autoimmune encephalitis patients’ blood. First, they used these antibodies in culture neural cells combined with electrophysiology and high-resolution techniques, and discovered that these antibodies will cause decrease of GluA2-containing AMPA receptors in the synapse. The decrease mainly resulted from two types of mechanisms: (1), which means bringing in the GluA2-containing AMPA receptors from the synapse into the cell; (2) Insertion of more non-GluA2-containing AMPA receptors onto the post-synaptic side of the synapse. As we have discussed before, the GluA2 subunit determines AMPA receptor’s function and underlies LTP, so this result made investigators wonder how GluA2-targetting antibodies would interfere with neuron’s normal function and animal’s behaviors. In the second part of the paper, researchers tried two ways, pump infusion or needle injection, to introduce GluA2-targetting antibodies into live mice’s brain. Not surprisingly, they found that LTP is severely impaired in these mice’s (which is a brain region controlling learning and memory). These mice also present memory deficits and anxiety-like behaviors resembling autoimmune encephalitis patients. Also, more importantly, researchers confirmed that decrease of GluA2-containing AMPA receptors and increase of non-GluA2-containing AMPA receptors do exist in these mice’s synapse, which implies that it is this mechanism that causes those encephalitis-like symptoms.
This new paper has given us a full picture of what GluA2-targetting antibodies could do on normal functioning AMPA receptors in the brain, and how it would link to abnormal signal transmission between neurons and disease-like symptoms. However, there still remain some unanswered questions. First, people would be curious about how the binding of antibodies to GluA2-containing AMPA receptors triggers their internalization. Although this paper gives us a hint that a protein calledthat anchors AMPA receptor is the first to be dissociated from the synapse, more detailed mechanism of the antibody-induced endocytosis is still mysterious. Second, what causes the increase of non-GluA2-containing AMPA receptors in synapse is unclear. It seems that more subunits (which has different ion gating function than GluA2) are inserted into the synapse in a compensatory manner, but the underlying molecular mechanism hasn’t been fully explored in this paper. Third, given the difference between GluA1 and GluA2 subunits of AMPA receptor (explained by a paper by ), it will be worthwhile to further explore how the change of AMPA receptor composition contribute to the impairment of LTP, and also learning and memory.
The investigation of the wronged AMPA receptor in autoimmune encephalitis reveals a kind of novel neuro-immune interaction, which will certainly become a basis for people to further understand the disease and develop new treatment. Optimistically, soon the wronged neural signal receptors won’t be threatened by antibodies anymore with medical interference!
The original research paper by Haselmann et al. can be found.
Another introduction of this paper can be found.