Enzyme Key To Learning Identified
The researchers zeroed in on the enzymes that manipulate a key scaffolding protein for synapses, the connections through which brain cells communicate. Synapses are weakened and lost in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.
“We identified a major underlying mechanism through which synapses are strengthened and maintained,” said Morgan H. Sheng, Menicon Professor of Neuroscience at MIT’s Picower Institute for Learning and Memory. “The enzymes involved could be good targets for potential drug treatments.”
A protein called postsynaptic density-95 (PSD-95) is a key building block of synapses. Like the steel girders in a building, it acts as a scaffold around which other components are assembled. “The more PSD-95 molecules, the bigger and stronger the synapse,” said co-author Myung Jong Kim, a Picower research scientist.
Previous research had shown that mice genetically altered to have less PSD-95 experienced learning and memory problems.
In the current study, the researchers identified for the first time the enzymes that work behind the scenes on PSD-95, adding a phosphate group to a specific amino acid in the PSD-95 protein. This process–called phosphorylation–is critical for PSD-95 to do its job in supporting synapses.
“Adding a phosphate group to a single amino acid allows PSD-95 to promote synapse size and strength,” said Sheng, who also holds an appointment in MIT’s Department of Brain and Cognitive Sciences and is a Howard Hughes Medical Institute investigator. “Therefore, promoting this process could help improve cognitive function.”
Sheng believes manipulating PSD-95 through phosphorylation could lead to bigger and more robust synapses, which would boost brainpower in both normal and diseased brains. “It’s possible that promoting PSD-95 phosphorylation could also help neuropsychiatric illnesses in which synapse function goes awry, such as schizophrenia, depression and autism,” Sheng said.
Neuron. 2007 Nov 8;56(3):488-502.
The Picower Institute for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
The scaffold protein PSD-95 promotes the maturation and strengthening of excitatory synapses, functions that require proper localization of PSD-95 in the postsynaptic density (PSD). Here we report that phosphorylation of ser-295 enhances the synaptic accumulation of PSD-95 and the ability of PSD-95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. We present evidence that a Rac1-JNK1 signaling pathway mediates ser-295 phosphorylation and regulates synaptic content of PSD-95. Ser-295 phosphorylation is suppressed by chronic elevation, and increased by chronic silencing, of synaptic activity. Rapid dephosphorylation of ser-295 occurs in response to NMDA treatment that causes chemical long-term depression (LTD). Overexpression of a phosphomimicking mutant (S295D) of PSD-95 inhibited NMDA-induced AMPA receptor internalization and blocked the induction of LTD. The data suggest that synaptic strength can be regulated by phosphorylation-dephosphorylation of ser-295 of PSD-95 and that synaptic depression requires the dephosphorylation of ser-295.