The chemical pathways to memory
Neurotransmission and its molecular basis are important in neuroscience as the basis for therapies for diseases such as Alzheimer's and how to maximise learning. As regards memory, long term potentiation (LTP) is thought to represent a substrate for memory formation in the brain. Researchers from the 'Sumoylation and kainate receptor synaptic plasticity' (Sumokainate) project have recently completed an investigation into learning, memory and synaptic plasticity. Two main pathways that lead to LTP have been elucidated. First, the team used a recently discovered compound, 77-LH-28-1, that can bind onto a muscarinic acetylcholine receptor (mAChR), part of a family of molecules that plays a major role in enhancing cognitive function. The molecule 77-LH-28-1 is significant in that it can bind onto a mAChR, thereby opening another receptor, N-methyl-D-aspartate (NMDA). Research has shown this is a predominant molecular device for controlling synaptic plasticity and memory function. It therefore qualifies as a candidate for treatment of Alzheimer's disease. A new technique developed by the Sumokainate team, dynamic clamping, is a refinement of patch clamping. The technique allows the emulation of activity or inhibition of ion channels at the cell's membrane. Data collected during dynamic clamping shows that a phenomenon known as after-depolarisation plays a role in LTP induction. After-depolarisation means the cell is more excitable than normal. Project scientists showed that another pathway, revealed by the inhibitor XE-991 that acts on Kv7 channels, enhances neural excitability. Kv7 inhibition therefore promotes NMDA receptor opening and in turn facilitates LTP. Perhaps the most exciting part of the Sumokainate research was investigation into the role of sumoylation in synaptic scaling, a form of synaptic plasticity. Synaptic scaling acts in a negative feedback manner to stabilise neuron firing. Sumoylation is the addition of small proteins to a protein to modify its function. Cells were treated with the protein neurotoxin tetrodotoxin (TTX) to prevent synaptic activity. Project data obtained after application of biochemical techniques to modulate sumoylation showed that this process does indeed play a part in homeostatic synaptic scaling of responses. To date, the role of sumoylation has been largely unknown outside the nucleus. Project results have therefore provided a novel mechanism for sumoylation that underlies synaptic plasticity.