Human behavior is a reflection of brain function. Our emotions, our intelligence, and our ability to learn and remember all depend on the intricacy of communication between trillions of nerve cells in the human brain. These neuronal circuits or pathways are sculpted by the constant modification of synaptic connections between neurons. These 'synapses' are specialized areas of contact in which signals are sent and received between two neurons. Active neurons release chemical signals, or neurotransmitters, at synapses, which travel across the narrow synaptic cleft between the neurons and bind to specific receptor molecules that activate the neighboring neuron.

    Each of the trillion neurons in the human brain can have up to 1000 synaptic connections. By establishing an ever-changing network of synapses, the brain is able to attain the level of functional complexity that underlies human behavior. The efficiency of the transmission of signals at synapses is constantly being adapted in response to surrounding neuronal activity. This constant change in the synaptic communication between neurons is called 'synaptic plasticity' and is critical for higher brain functions such as learning and memory.

    Our laboratory is interested in the mechanisms that regulate synaptic transmission and synaptic plasticity. The general approach we have taken is to study molecular and cellular mechanisms that regulate neurotransmitter receptors. These receptors mediate the response of neurons to neurotransmitters released at synapses and are a central convergence point for transmission of signals between neurons. Modulation of the function of these receptors is a powerful and efficient way to modulate synaptic communication and synaptic plasticity. Over the years we have shown that receptor protein phosphorylation and the regulation of the synaptic targeting of receptors are dynamically regulated and regulate the efficiency of synaptic transmission. We are currently focusing our efforts on the mechanisms that underlie the regulation of the glutamate receptors, the major excitatory neurotransmitter receptors in the brain. These receptors are neurotransmitter-dependent ion channels that allow ions to pass through the neuronal cell membrane, resulting in the excitation of neuronal activity.

    Previous studies in our laboratory have shown that the function of neurotransmitter receptors can be highly regulated by several cellular mechanisms, including a process called protein phosphorylation. Protein phosphorylation occurs when protein kinase enzymes catalyze the chemical transfer of phosphate molecules from ATP to a specific substrate protein such as a receptor molecule. The addition of the negatively charged phosphate group alters the structure of the receptor and can regulate its functional properties. Protein phosphorylation is a reversible process; enzymes called protein phosphatases can remove the phosphate group from the receptor. Protein phosphorylation and dephosphorylation are highly regulated processes and thus the level of receptor phosphorylation in a neuron is constantly modified by neurotransmitters and hormones released by the surrounding neurons.
    More recent work in our laboratory has focused on the role of protein phosphorylation in the regulation of glutamate receptor function. Glutamate receptors are one of the most important receptor systems in the brain and play critical roles in learning and memory, development of the brain, and neurological disorders. These receptors come in many different subtypes and are classified based on their pharmacological and physiological properties into N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. In our studies we have found that protein phosphorylation of these receptors is extremely complex, and individual subunits can be multiply phosphorylated by several protein kinases and dephosphorylated by a variety of protein phosphatases. Each of these phosphorylation events can regulate the receptors in distinct ways. For example, the NMDA subtype of glutamate receptors is phosphorylated by at least three distinct types of protein kinases and phosphorylation of the NMDA receptor by one of these kinases appears to regulate the subcellular distribution of the receptor in cells. In addition, recent studies in our lab have shown that the phosphorylation of AMPA receptors by protein kinases potentiates the responsiveness of the receptor to glutamate and thus enhances the efficiency of synaptic transmission.
    Currently we are investigating whether the phosphorylation of glutamate receptors is involved in the mechanisms underlying well-characterized models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are processes in the brain in which the communication between neurons can be rapidly modified by surrounding neuronal activity to produce long lasting changes in the efficiency of synaptic transmission. It is these long lasting changes in neuronal connections that sculpt the neuronal circuits that are thought to underlie learning and memory. Our recent data has shown that the phosphorylation of the AMPA receptor changes during LTP and LTD and that receptor phosphorylation may directly mediate changes in synaptic connectivity in these cellular models of learning and memory.

    The presence of high concentrations of receptors in the cell membrane at synaptic connections is critical for the efficient transmission of signals between neurons. Neurotransmitter receptors are specifically transported by the cell and localized at synapses by a complex synaptic scaffold. The regulation of this 'synaptic targeting' may be important for synaptic plasticity. Recently we have been examining the molecular mechanisms that regulate the targeting of glutamate receptors to synapses. We have identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors.

    GRIPs contain seven PDZ domains, protein-protein interaction motifs, which appear to crosslink AMPA receptors or link them to other proteins. In addition, we have recently found that the C-termini of GluR2 also interact with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. Finally, the GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins appear to be involved in the proper subcellular targeting and synaptic clustering of these receptors. In addition to these studies on AMPA receptors, we have been characterizing a separate NMDA receptor associated protein complex that appears to be involved in synaptic targeting and downstream signaling of NMDA receptors. We have recently identified an excitatory synapse specific rasGAP, which we call synGAP, that associates with the NMDA receptor complex and appears to be involved in the regulation of synaptic ras signaling by NMDA receptors.

    In summary, our laboratory has been investigating the molecular mechanisms in the regulation of neurotransmitter receptor function. Our studies of neurotransmitter receptors, including the major excitatory receptors in brain, the glutamate receptors, demonstrate that protein phosphorylation of receptors is a major mechanism for the control of their function and is critical for the regulation of synaptic communication. Moreover, recent studies on the regulation of the synaptic localization of receptors have shown that receptor interacting proteins, such as GRIP, PICK1, NSF and synGAP, may be significant modulators of synaptic plasticity. These studies provide evidence that the regulation of neurotransmitter receptor function plays a central role in the modulation of synaptic transmission and may be an important determinant in brain function and human behavior.