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Researchers in Germany have found a potential new cause of seizure activity in the brain, involving a protein known as PRG-1 (named after the gene that encodes it, Plasticity Related Gene-1).
The team, based at Charité Universitätsmedizin Berlin, was in fact the first to discover PRG-1 in an earlier study. They were especially intrigued by this protein, because it was only found in the brain, and more specifically in the membranes of neurons in the hippocampus (an important memory centre). This is highly unusual, because the majority of molecules are found in most cells of the body, albeit in different quantities.
In the current study, the investigators wanted to explore the functions of PRG-1. One of the best ways to find out the role of a molecule is to see what happens when it is 'missing' from the body.
They therefore bred animals that lacked the PRG-1 gene (and so didn't produce any PRG-1) and examined the effects. Interestingly, they found that the models developed severe seizures soon after birth.
When the group examined the electrical activity in the brains of these models, they found an increase in excitatory activity compared to normal, but no change in inhibitory activity.
This suggests that PRG-1 regulates excitatory activity in the brain and prevents it from becoming 'too much'. Removal of this calming effect led to hyperexcitation of neurons and seizure activity. The fact that inhibitory activity remained unchanged suggests that PRG-1 is not involved with inhibition.
The researchers then applied PRG-1 protein to the brains of PRG-1 deficient models, whilst they were developing, and tracked its activity. They found that the PRG-1 acted specifically at the post-synaptic membranes of excitatory neurons in the hippocampus, regulating excitatory activity and preventing hyperexcitability.
Earlier studies have shown that PRG-1 acts by regulating signalling molecules called phospholipids and lysophospholipids; so it is likely that PRG-1 controls brain excitability in this way. It is also known that PRG-1 is related to a family of proteins that inactivate a lysophospholipid called lysophosphatidic acid (LPA), which plays an important role in brain development. The group's next step was to find out if LPA has a role in brain hyperexcitation.
They used developing models again, but instead of applying normal PRG-1 to their brains, they created a mutant form of PRG-1 that was unable to interact with LPA. This led to hyperexcitability in the neurons affected. Not being able to interact with LPA had abolished PRG-1's ability to 'calm' the brain and prevent too much excitation.
We can gather from these results that LPA must be responsible for increasing excitation in the activity of excitatory neurons, and that PRG-1 prevents over excitation.
The likely way in which LPA increases excitation is to increase the amount of glutamate released onto excitatory neurons.
How does it do this? LPA is located outside of the nerve, but can influence activity in the nerve terminal by acting on receptors. LPA can bind at least five different receptors, but the effects of each are slightly different. From existing knowledge, the researchers were able to predict which receptor LPA must bind to in order to increase the release of glutamate from the pre-synaptic membrane. This is a receptor known as LPA2.
In the final stage of the study, the team bred animals that lacked both PRG-1 and LPA2. They wanted to see if LPA2 is needed in order for LPA to increase excitation. If so, a lack of both LPA2 and PRG-1 should not result in seizures, because there will be no hyperexcitation. Sure enough, these models did not experience seizures.
To summarise these results: It is likely that PRG-1 in the post-synaptic membrane regulates excitatory activity that is caused by the interaction between LPA outside the nerve and LPA2 on the pre-synaptic membrane. It probably does this by removing some of the LPA from around the synapse and inactivating it.
Is PRG-1 function the same in humans as in these animal models? More investigation needs to be done, but if so, this could possibly be a cause of epilepsy. New treatments that compensate for a lack of PRG-1 could potentially help to prevent seizures in the future.
The team, based at Charité Universitätsmedizin Berlin, was in fact the first to discover PRG-1 in an earlier study. They were especially intrigued by this protein, because it was only found in the brain, and more specifically in the membranes of neurons in the hippocampus (an important memory centre). This is highly unusual, because the majority of molecules are found in most cells of the body, albeit in different quantities.
In the current study, the investigators wanted to explore the functions of PRG-1. One of the best ways to find out the role of a molecule is to see what happens when it is 'missing' from the body.
They therefore bred animals that lacked the PRG-1 gene (and so didn't produce any PRG-1) and examined the effects. Interestingly, they found that the models developed severe seizures soon after birth.
When the group examined the electrical activity in the brains of these models, they found an increase in excitatory activity compared to normal, but no change in inhibitory activity.
This suggests that PRG-1 regulates excitatory activity in the brain and prevents it from becoming 'too much'. Removal of this calming effect led to hyperexcitation of neurons and seizure activity. The fact that inhibitory activity remained unchanged suggests that PRG-1 is not involved with inhibition.
The researchers then applied PRG-1 protein to the brains of PRG-1 deficient models, whilst they were developing, and tracked its activity. They found that the PRG-1 acted specifically at the post-synaptic membranes of excitatory neurons in the hippocampus, regulating excitatory activity and preventing hyperexcitability.
Earlier studies have shown that PRG-1 acts by regulating signalling molecules called phospholipids and lysophospholipids; so it is likely that PRG-1 controls brain excitability in this way. It is also known that PRG-1 is related to a family of proteins that inactivate a lysophospholipid called lysophosphatidic acid (LPA), which plays an important role in brain development. The group's next step was to find out if LPA has a role in brain hyperexcitation.
They used developing models again, but instead of applying normal PRG-1 to their brains, they created a mutant form of PRG-1 that was unable to interact with LPA. This led to hyperexcitability in the neurons affected. Not being able to interact with LPA had abolished PRG-1's ability to 'calm' the brain and prevent too much excitation.
We can gather from these results that LPA must be responsible for increasing excitation in the activity of excitatory neurons, and that PRG-1 prevents over excitation.
The likely way in which LPA increases excitation is to increase the amount of glutamate released onto excitatory neurons.
How does it do this? LPA is located outside of the nerve, but can influence activity in the nerve terminal by acting on receptors. LPA can bind at least five different receptors, but the effects of each are slightly different. From existing knowledge, the researchers were able to predict which receptor LPA must bind to in order to increase the release of glutamate from the pre-synaptic membrane. This is a receptor known as LPA2.
In the final stage of the study, the team bred animals that lacked both PRG-1 and LPA2. They wanted to see if LPA2 is needed in order for LPA to increase excitation. If so, a lack of both LPA2 and PRG-1 should not result in seizures, because there will be no hyperexcitation. Sure enough, these models did not experience seizures.
To summarise these results: It is likely that PRG-1 in the post-synaptic membrane regulates excitatory activity that is caused by the interaction between LPA outside the nerve and LPA2 on the pre-synaptic membrane. It probably does this by removing some of the LPA from around the synapse and inactivating it.
Is PRG-1 function the same in humans as in these animal models? More investigation needs to be done, but if so, this could possibly be a cause of epilepsy. New treatments that compensate for a lack of PRG-1 could potentially help to prevent seizures in the future.
