Page - (000285) - in Biomedical Chemistry: Current Trends and Developments

appear to increase the population of expressed NMDA receptors containing the NR2B subunit and the number of metabotropic mGluR5 receptors present at the synapse, which could also lead to excitotoxicity. Recent research has also suggested that extrasynaptic NMDA receptor activation could lead to an increase in Aβ production, unlike synaptic NMDA receptor activity. Further complicating matters is the fact that the different groups (group I and group II) of metabotropic glutamate receptors (mGluRs) have differing effects on Aβ production by neurons (Hu, 2012). Further, two observed effects of Aβ are not directly linked to excitotoxicity, but further implicate glutamatergic transmission in AD. When cultures of neurons that were collected from the hippocampus, an area of the brain critical to memory formation, were exposed to sub- nanomolar concentrations of Aβ, it was found to promote glutamate release in an activity dependent manner. While this may possibly be a normal function as it would support the cellular and molecular processes underlying learning and memory, other experiments on hippocampal neurons found that high nanomolar concentrations of Aβ clusters bind to the postsynaptic spines of glutamatergic synapses. This binding is associated with the internalization of AMPA receptors, which can lead to the loss of the synaptic spine, and thus that synaptic connection. This synaptic loss would reduce the ability of affected neurons to communicate with each other, and could impair the neuronal connections that support memory formation and maintenance. There is also some evidence that hyperphosphorylated tau may interfere with iGluR trafficking, which could also impair synaptic formation and maintenance (Hu, 2012). 3.2.6.4 Huntington’s Disease (HD) Huntington’s disease is an inherited degenerative disorder that results in the death of cortical and striatal neurons, specifically certin GABA- releasing neurons known as GABAergic medium-sized spiny neurons (Mony, 2009). The loss of these neurons results in a range of physical, psychological, and cognitive symptoms. Involuntary spastic movement and difficulty initiating and controlling voluntary movement are common in the early stages of this progressive disorder. These