A novel role for NMDA receptors in brain plasticity and learning
Signals transmitted between the brain’s nerve cells or neurons use synapses – the tiny gaps between neurons – to communicate. Synapses can change and adapt over time, a process known as plasticity, which is also crucial for memory and learning. “Neurons are stimulated by synapses that drive some pattern of electrical activity which then communicates to other neurons. That’s how the brain network functions,” explains NovelNMDA project coordinator Brett Carter, from the European Neuroscience Institute(opens in new window) at the University Medical Center(opens in new window) Göttingen, Germany. The NovelNMDA project was funded by the European Research Council(opens in new window). When ‘excited’ or stimulated, the sending cell generates an electrical signal which converts into a chemical neurotransmitter, in this case glutamate, that interacts with receptors on the receiving cell. So-called N-methyl-D-aspartate (NMDA) receptors are present in most glutamatergic synapses. “If we can understand how NMDA signals, then maybe we could target it, with other experiments or using pharmacology, to change how synaptic plasticity happens,” Carter notes. Longer term, this fundamental research could be useful for developing more sophisticated ways to treat neurological conditions, for example, treating long-term depression.
Importance of calcium ions
When NMDA receptors are active, they open up a channel to let calcium ions flow in and out of the cell and change the electrical behaviour, Carter explains. “NMDA receptors have been a focus of research because that calcium is thought to be really important for biochemical signalling at synapses and for synaptic plasticity.” However, NMDA receptors can also bypass the calcium channel. “It may be independent of the calcium signals from these receptors – a novel way of signalling that hasn’t been appreciated before,” he notes. “What we think is, in addition to opening the ion channel when glutamate binds, it is sending some other signal to the inside of the cell which then leads to a biochemical cascade to signal long-term plasticity.”
Imaging techniques to identify calcium
Optical imaging techniques using fluorescent calcium-sensitive molecules were used to observe individual synapses. At the same time, the electrical signals generated by neurons were monitored using electrophysiology techniques in laboratory mice to see how the individual synapses were working and changing. “We used pharmacology to manipulate receptors in certain signalling pathways to see how it affected that electrophysiology measure,” says Carter, adding: “We made some headway on how this plasticity happens.” The team found that NMDA receptors have a novel signalling function independent of their ion channel activity, which appears to involve retrograde signalling and potentially influences synaptic plasticity in ways not previously understood. He points out that the drug ketamine, already used for treatment-resistant depression, “blocks the NMDA receptor ion channel function but leaves the other non-ionic function intact.” Past research has focused on post-synaptic changes, but plasticity also occurs in presynaptic or sending neurons, he says, as the EU-funded SYNPRIME project also found.
Focus on early development
Carter observes that rodent whiskers are important sensing organs connected to the somatosensory cortex – the part of the brain that processes sensory information such as touch, pain, temperature and physical awareness. Plasticity happens all the time, including at a later age. “But we focused on early developmental plasticity, a critical period of development where experience in the world changes the way the cells in the cortex function,” he adds. “In addition to long-term plasticity, we observed a peculiar short-term plasticity time course at the cortical synapses that shows depression developing over time.”
