Professional Education

  • Master of Medicine, Unlisted School (1997)
  • Doctor of Philosophy, University of Auckland (2012)

Stanford Advisors

All Publications

  • Array tomography of physiologically-characterized CNS synapses JOURNAL OF NEUROSCIENCE METHODS Valenzuela, R. A., Micheva, K. D., Kiraly, M., Li, D., Madison, D. V. 2016; 268: 43-52


    The ability to correlate plastic changes in synaptic physiology with changes in synaptic anatomy has been very limited in the central nervous system because of shortcomings in existing methods for recording the activity of specific CNS synapses and then identifying and studying the same individual synapses on an anatomical level.We introduce here a novel approach that combines two existing methods: paired neuron electrophysiological recording and array tomography, allowing for the detailed molecular and anatomical study of synapses with known physiological properties.The complete mapping of a neuronal pair allows determining the exact number of synapses in the pair and their location. We have found that the majority of close appositions between the presynaptic axon and the postsynaptic dendrite in the pair contain synaptic specializations. The average release probability of the synapses between the two neurons in the pair is low, below 0.2, consistent with previous studies of these connections. Other questions, such as receptor distribution within synapses, can be addressed more efficiently by identifying only a subset of synapses using targeted partial reconstructions. In addition, time sensitive events can be captured with fast chemical fixation.Compared to existing methods, the present approach is the only one that can provide detailed molecular and anatomical information of electrophysiologically-characterized individual synapses.This method will allow for addressing specific questions about the properties of identified CNS synapses, even when they are buried within a cloud of millions of other brain circuit elements.

    View details for DOI 10.1016/j.jneumeth.2016.04.017

    View details for Web of Science ID 000379104400006

    View details for PubMedID 27141856

  • beta-Amyloid Inhibits E-S Potentiation through Suppression of Cannabinoid Receptor 1-Dependent Synaptic Disinhibition NEURON Orr, A. L., Hanson, J. E., Li, D., Klotz, A., Wright, S., Schenk, D., Seubert, P., Madison, D. V. 2014; 82 (6): 1334-1345
  • ß-Amyloid inhibits E-S potentiation through suppression of cannabinoid receptor 1-dependent synaptic disinhibition. Neuron Orr, A. L., Hanson, J. E., Li, D., Klotz, A., Wright, S., Schenk, D., Seubert, P., Madison, D. V. 2014; 82 (6): 1334-1345


    It has been widely reported that β-amyloid peptide (Aβ) blocks long-term potentiation (LTP) of hippocampal synapses. Here, we show evidence that Aβ more potently blocks the potentiation of excitatory postsynaptic potential (EPSP)-spike coupling (E-S potentiation). This occurs, not by direct effect on excitatory synapses or postsynaptic neurons, but rather through an indirect mechanism: reduction of endocannabinoid-mediated peritetanic disinhibition. During high-frequency (tetanic) stimulation, somatic synaptic inhibition is suppressed by endocannabinoids. We find that Aβ prevents this endocannabinoid-mediated disinhibition, thus leaving synaptic inhibition more intact during tetanic stimulation. This intact inhibition opposes the normal depolarization of hippocampal pyramidal neurons that occurs during tetanus, thus opposing the induction of synaptic plasticity. Thus, a pathway through which Aβ can act to modulate neural activity is identified, relevant to learning and memory and how it may mediate aspects of the cognitive decline seen in Alzheimer's disease.

    View details for DOI 10.1016/j.neuron.2014.04.039

    View details for PubMedID 24945775

    View details for PubMedCentralID PMC4114400

  • Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-Neuroligin-Mediated Transsynaptic Signaling JOURNAL OF NEUROSCIENCE Arons, M. H., Thynne, C. J., Grabrucker, A. M., Li, D., Schoen, M., Cheyne, J. E., Boeckers, T. M., Montgomery, J. M., Garner, C. C. 2012; 32 (43): 14966-14978


    Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.

    View details for DOI 10.1523/JNEUROSCI.2215-12.2012

    View details for Web of Science ID 000310523900013

    View details for PubMedID 23100419

    View details for PubMedCentralID PMC3752148

  • SAP97 directs NMDA receptor spine targeting and synaptic plasticity JOURNAL OF PHYSIOLOGY-LONDON Li, D., Specht, C. G., Waites, C. L., Butler-Munro, C., Leal-Ortiz, S., Foote, J. W., Genoux, D., Garner, C. C., Montgomery, J. M. 2011; 589 (18): 4491-4510


    SAP97 is a multidomain scaffold protein implicated in the forward trafficking and synaptic localization of NMDA- and AMPA-type glutamate receptors. Alternative splicing of SAP97 transcripts gives rise to palmitoylated αSAP97 and L27-domain containing βSAP97 isoforms that differentially regulate the subsynaptic localization of GluR1 subunits of AMPA receptors. Here, we examined whether SAP97 isoforms regulate the mechanisms underlying long-term potentiation (LTP) and depression (LTD) and find that both α- and β-forms of SAP97 impair LTP but enhance LTD via independent isoform-specific mechanisms. Live imaging of α- and βSAP97 revealed that the altered synaptic plasticity was not due to activity-dependent changes in SAP97 localization or exchange kinetics. However, by recording from pairs of synaptically coupled hippocampal neurons, we show that αSAP97 occludes LTP by enhancing the levels of postsynaptic AMPA receptors, while βSAP97 blocks LTP by reducing the synaptic localization of NMDA receptors. Examination of the surface pools of AMPA and NMDA receptors indicates that αSAP97 selectively regulates the synaptic pool of AMPA receptors, whereas βSAP97 regulates the extrasynaptic pools of both AMPA and NMDA receptors. Knockdown of βSAP97 increases the synaptic localization of both AMPA and NMDA receptors, showing that endogenous βSAP97 restricts glutamate receptor expression at excitatory synapses. This isoform-dependent differential regulation of synaptic versus extrasynaptic pools of glutamate receptors will determine how many receptors are available for the induction and the expression of synaptic plasticity. Our data support a model wherein SAP97 isoforms can regulate the ability of synapses to undergo plasticity by controlling the surface distribution of AMPA and NMDA receptors.

    View details for DOI 10.1113/jphysiol.2011.215566

    View details for Web of Science ID 000295050800011

    View details for PubMedID 21768261

    View details for PubMedCentralID PMC3208220

  • Synaptic SAP97 Isoforms Regulate AMPA Receptor Dynamics and Access to Presynaptic Glutamate JOURNAL OF NEUROSCIENCE Waites, C. L., Specht, C. G., Haertel, K., Leal-Ortiz, S., Genoux, D., Li, D., Drisdel, R. C., Jeyifous, O., Cheyne, J. E., Green, W. N., Montgomery, J. M., Garner, C. C. 2009; 29 (14): 4332-4345


    The synaptic insertion of GluR1-containing AMPA-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, mechanisms responsible for GluR1 insertion and retention at the synapse are unclear. The synapse-associated protein SAP97 directly binds GluR1 and participates in its forward trafficking from the Golgi network to the plasma membrane. Whether SAP97 also plays a role in scaffolding GluR1 at the postsynaptic membrane is controversial, attributable to its expression as a collection of alternatively spliced isoforms with ill-defined spatial and temporal distributions. In the present study, we have used live imaging and electrophysiology to demonstrate that two postsynaptic, N-terminal isoforms of SAP97 directly modulate the levels, dynamics, and function of synaptic GluR1-containing AMPARs. Specifically, the unique N-terminal domains confer distinct subsynaptic localizations onto SAP97, targeting the palmitoylated alpha-isoform to the postsynaptic density (PSD) and the L27 domain-containing beta-isoform primarily to non-PSD, perisynaptic regions. Consequently, alpha- and betaSAP97 differentially influence the subsynaptic localization and dynamics of AMPARs by creating binding sites for GluR1-containing receptors within their respective subdomains. These results indicate that N-terminal splicing of SAP97 can control synaptic strength by regulating the distribution of AMPARs and, hence, their responsiveness to presynaptically released glutamate.

    View details for DOI 10.1523/JNEUROSCI.4431-08.2009

    View details for Web of Science ID 000265009600002

    View details for PubMedID 19357261

    View details for PubMedCentralID PMC3230533