Long-term changes in synaptic strength, such as long-term potentiation (LTP) and long-term depression (LTD), have been proposed to be the cellular correlates of learning and memory formation. In the hippocampus, an area of the brain associated with memory formation, LTP and LTD require functional modification of AMPA receptors (AMPARs). Since AMPARs are the major ionotropic glutamate receptors in the brain, changing the single channel properties and/or the number at synapses can greatly affect excitatory synaptic function. Recent studies highlight that functional recruitment of Ca2+-permeable AMPARs (CP-AMPARs) at synapses is another key regulatory mechanism that alter excitatory synaptic transmission.

By combining electrophysiology, biochemistry, and imaging methods, I found that phosphorylation of the GluR1 subunit of AMPAR on the serine-845 site (GluR1-S845) is critical for the functional recruitment of CP-AMPARs. This has functional consequences as CP-AMPARs can be expressed at synapses by various neuronal activities both in vitro and in vivo, such as by LTP, sensory experiences, brain diseases and drug addiction. On the other hand, dephosphorylation of the GluR1-S845 is necessary for producing long-term synaptic depression, which is accompanied by a loss in functional CP-AMPARs. Interestingly, the GluR1-S845 site is not required for the plasticity of dendritic spine structures, which is considered an important mechanism for long-term synaptic plasticity as well as learning and memory formation. These results suggest that the functional change in synaptic transmission and the structural synaptic plasticity may utilize separate signaling cascades.

In a parallel study, I demonstrated that the beta-site cleaving enzyme 1 (BACE1), which cleaves the amyloid precursor protein (APP) to release the amyloid beta peptide (Abeta), is also involved in regulating synaptic plasticity. Using mice lacking the BACE1 gene, I found that BACE1 is involved in specific forms of synaptic plasticity as well as presynaptic function. Abnormal accumulation of Abeta by excessive BACE1 activity is thought responsible for triggering the pathology of Alzheimer's disease (AD). However, my results caution the development of AD therapeutics targeting the BACE1 activity.

In summary, my studies demonstrate that the function of AMPA receptors can be regulated in multiple ways, including phosphorylation of a single amino acid, and is critically involved in synaptic plasticity that underlies learning and memory formation.