Research

 
 
 

    AMPA receptors are ionotropic glutamate-gated cation channels that conduct the major fast currents at excitatory synapses. AMPARs are homo and heterotetramers of the GluR1, -2, -3 and -4 subunits. AMPAR trafficking pathways control the number of AMPARs at synapses and thereby regulate synapse strength (reviewed by Barry and Ziff, 2002 (PDF)). NMDA receptors are a related family of glutamatergic ionotopic receptors that couple synapse activity to synapse plasticity. We study the mechanisms that enable synapse activity to control the synaptic populations of AMPARs through receptor trafficking.
    Trafficking of GluR1: We have found that the NMDAR regulates GluR1 levels in the plasma membrane through a novel pathway involving nitric oxide and GluR1 phosphorylation. NMDARs induce the cGMP regulated protein kinase, cGKII, which phosphorylates the GluR1 AMPAR subunit on serine 845 in the C-terminal domain and increases GluR1 plasma membrane levels. NMDAR activation of neuronal nitric oxide synthase and the NO-dependent production of cGMP are intermediates in this control. We are investigating the mechanisms that enable cGKII to phosphorylate GluR1 and how this phosphorylation contributes to increases in synaptic strength (Serulle et al., 2007 (PDF, Figure))
    Trafficking of GluR2: We have found that the GluR2 AMPAR subunit binds a specialized group of scaffolding and trafficking proteins that govern GluR2 movement to and from synapses. These GluR2-binding proteins include the PDZ domain-containing scaffolds, GRIP and ABP (Srivastava et al., 1998), as well as the trafficking protein, PICK1 (Perez et al., 2001 (PDF)) , and the specialized chaperone, NSF (Osten et al., 2000 (PDF)). We study how GluR2 subunits can shift from anchorage to internal scaffolds to anchorage to synaptic scaffolds as a step in trafficking between these locations (Hanley et al, 2002 (PDF); Lu et al., 2005 (PDF).  We are also studying how synaptic activity can regulate this shift, in particular the role of Ca2+ fluxes in controlling GluR2 trafficking. (Figure)

    Synaptic Control of Reward System Function: Medium Spiny Neurons  are GABAergic neurons that make up the majority of the striatum, and which function in the organism’s  behavioral responses to reward. MSNs receive glutamatergic input from several brain areas including cortex that conveys information about environment, and dopaminergic input from the ventral tegmental area (VTA) that conveys information about body state and reward. The synergy of these inputs controls MSN synapse function, which in turn controls motor systems and behavior. We study how dopamine and glutamate interact functionally at MSN synapses and how this control is implemented by natural rewards, such as sucrose.

 

AMPA RECEPTOR TRAFFICKING AND THE CONTROL OF SYNAPSE STRENGTH

SPINE AND SYNAPSE MORPHOGENESIS

NEUROLOGICAL DISEASE

          In hippocampal pyramidal neurons and other neuron types, glutamatergic synapses are located at the heads of spines, which are specialized dendritic structures that compartmentalize glutamatergic synapse activity. (Figure)

            AMPAR Scaffolds: AMPARs are anchored at synapses through interaction with specialized scaffolds. We study the specialized scaffolds, ABP and GRIP, which are multi-PDZ proteins that bind GluR2 and Eph receptors and Ephrins as well as other synaptic proteins (Srivastava, et al, 1998 (PDF)). ABP and GRIP connect GluR2 to the cadherin cell adhesion protein complex through binding to Neural Plakophilin Related ARM Protein (NPRAP; delta catenin), a cadherin-associated protein (Silverman et al., 2007 (PDF)). Notably, we find that NPRAP can also induce actin polymerization and contribute to spine morphogenesis. (Diagram).

            PSD Proteins: The postsynaptic density is a specialize complex of cytoskeletal, and regulatory proteins found at the heads of spines (reviewed by Ziff, 1997 (PDF)). The PSD functions in anchoring AMPARs at synapses and contributes to the establishment of spine morphology. We have used mass spectrometry to identify components of the PSD (Jordan et al, 2004 (PDF)). We study regulatory functions of PSD components, including AIDA (Jordan et al., 2007 (PDF)) and the ARF GEF, IQsec, whose expression stimulates spine maturation. (Figure)

          In hippocampal pyramidal neurons and other neuron types, glutamatergic synapses are located at the heads of spines, which are specialized dendritic structures that compartmentalize glutamatergic synapse activity. (Figure)

            AMPAR Scaffolds: AMPARs are anchored at synapses through interaction with specialized scaffolds. We study the specialized scaffolds, ABP and GRIP, which are multi-PDZ proteins that bind GluR2 and Eph receptors and Ephrins as well as other synaptic proteins (Srivastava, et al, 1998 (PDF)). ABP and GRIP connect GluR2 to the cadherin cell adhesion protein complex through binding to Neural Plakophilin Related ARM Protein (NPRAP; delta catenin), a cadherin-associated protein (Silverman et al., 2007 (PDF)). Notably, we find that NPRAP can also induce actin polymerization and contribute to spine morphogenesis. (Diagram).

            PSD Proteins: The postsynaptic density is a specialize complex of cytoskeletal, and regulatory proteins found at the heads of spines (reviewed by Ziff, 1997 (PDF)). The PSD functions in anchoring AMPARs at synapses and contributes to the establishment of spine morphology. We have used mass spectrometry to identify components of the PSD (Jordan et al, 2004 (PDF)). We study regulatory functions of PSD components, including AIDA (Jordan et al., 2007 (PDF)) and the ARF GEF, IQsec, whose expression stimulates spine maturation. (Figure)