Molecular basis for recovery after neuronal lesion
30 March 2021. The ability of the brain to adapt to its environment (its “plasticity”) is absolutely essential for its proper development and function -impaired plasticity is increasingly associated with neurodevelopmental disorders (such as schizophrenia or autism spectrum disorders), and failing plasticity mechanisms also underlie neurodegenerative diseases (e.g. Alzheimer's or Parkinson's disease). It is therefore essential to understand how the brain can adapt - and why it sometimes fails to do so.
Scientists at Goethe University Frankfurt report in the current issue of the scientific journal Cell Reports that they have uncovered a molecular interaction that supports plasticity after a neuronal lesion. This interaction can promote neuronal recovery when stimulated - a discovery that opens up new therapeutic perspectives.
Neurons can adapt their function to changes in their environment by changing the number and shape of distinct protrusions, the so-called “spines”, which serve as the main site of input from connected neurons. They can also adjust the number of molecules on these spines (called "receptors") that receive and process information coming from these connected neurons.
Amparo Acker-Palmer's team at BMLS and the Institute of Cell Biology and Neuroscience at Goethe University Frankfurt focused their study on the main type of excitatory receptors, called AMPA receptors. They studied a specific type of plasticity induced by a neuronal lesion that mimics brain injury, and they assessed the dynamic changes after this lesion in AMPA receptor distribution and in the number and shape of spines. They discovered that a neuronal lesion leads to a dramatic change in both factors, and that these factors slowly return to their original values over time thanks to neuronal plasticity.
The researchers also found that this plasticity depends on the interaction of AMPA receptors with two proteins, GRIP1 and ephrinB2. When they impair GRIP1 or ephrinB2 function, recovery from lesion-induced changes is incomplete, suggesting that this macromolecular complex regulates the morphological (number and shape of spines) and functional (distribution of AMPA receptors) changes that are important for recovery after a neuronal lesion. This is particularly interesting because they have previously shown that GRIP1 and ephrinB2 also mediate AMPA receptor dynamics in the plasticity mechanisms that underlie learning and memory. Thereby the team of Amparo Acker-Palmer could show that the same complex supports multiple processes crucial for brain function.
In addition, stimulating ephrinB2 can prevent lesion-induced changes or, most importantly, rescue the impaired recovery in GRIP1 mutants, where GRIP1 function is altered. Because this stimulation can be achieved with a soluble factor that specifically binds ephrinB2, these fascinating results offer new avenues to improve neuronal function after brain injury.
Contact:
Amparo Acker-Palmer, Buchmann Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Acker-Palmer(at)bio.uni-frankfurt.de
Publication:
Diane Bissen, Maximilian K. Kracht, Franziska Foss, Jan Hofmann and Amparo Acker-Palmer (2021) EphrinB2 and GRIP1 stabilize mushroom spines during denervation-induced homeostatic plasticity. Cell Reports, published online 30 March 2021 https://doi.org/10.1016/j.celrep.2021.108923.