Keep your synapses together

Synapses are junctions at which nerve cells transfer information to one another or to muscle or gland cells. Electrical impulses from the pre-synaptic neuron, or nerve cells of the brain, are converted into chemical signals called neurotransmitters that travel across the gap between cells and are received by receptors on the opposite side. Immediately behind the membrane of the post-synaptic cell is an elaborate mix of proteins called the post-synaptic density (PSD). These proteins serve to anchor and traffic neurotransmitter receptors to the cell membrane and secure various receptor-modulating molecules. Because PSD-95 helps to strengthen and mature synapses, it has been of specific interest to Morgan Sheng and his team at the RIKEN-MIT Neuroscience Research Center in Cambridge, Massachusetts, The Picower Institute for Learning and Memory also at MIT, US, and the University of Bristol, UK. In the brain, PSD-95 is modified by the introduction of a phosphate group, a process known as phosphorylation, on one of its amino acid residues, serine-295. The researchers studied how phosphorylation regulates synaptic function. As reported recently in Neuron¹, they found that the addition of a phosphate group ushers the protein to part of the synapse where it can stabilize receptors that receive neurotransmitters and activate the post-synaptic cell. Sheng and his team created mutant proteins that either mimicked phosphorylated PSD-95 or prevented phosphorylation and examined their effects in brain cells. The ‘phosphomimic’ mutant increased the level of neurotransmitter receptors on the surface of the post-synaptic cell compared to normal brain cells, whereas the non-phosphorylated mutant failed to increase receptor levels. The phosphomimic mutant was targeted to a particular area of the synapse that allowed it to promote the surface expression of receptors (Fig. 1). The researchers also describe, for the first time, a mechanism for the regulation of serine-95 phosphorylation. They found it is mediated mostly by an enzyme called Jun N-terminal kinase1 (JNK1) and dependent on another protein, Rac1. Phosphorylation is vital to synaptic targeting of the PSD-95 protein, whereas dephosphorylation is important for long-term depression of synaptic strength, which, for example, is important in learning and memory. “Boosting serine-295 phosphorylation should increase the amount of PSD-95 in synapses and might help to prevent the synapse weakening or synapse loss that is associated with certain neurodegenerative diseases, such as Alzheimer’s disease,” says Sheng.