Academic Appointments

Research & Scholarship

Current Research and Scholarly Interests

Aaron Milstein studies how dynamic synapses, neuronal cellular diversity, network connectivity, and plasticity mediate learning and memory. He trained with Roger Nicoll, Jeff Magee, and Sandro Romani, employing electrophysiology, optogenetics, pharmacology, and computational modeling to investigate information processing in neuronal circuits. Currently Aaron uses modern parallel computing methods to simulate spatial memory encoding in the hippocampus and its disfunction in epilepsy.


All Publications

  • Persistent Sodium Current Mediates the Steep Voltage Dependence of Spatial Coding in Hippocampal Pyramidal Neurons. Neuron Hsu, C., Zhao, X., Milstein, A. D., Spruston, N. 2018


    The mammalian hippocampus forms a cognitive map using neurons that fire according to an animal's position ("place cells") and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses invivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of invitro, invivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.

    View details for PubMedID 29909995

  • Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells. Nature neuroscience Grienberger, C., Milstein, A. D., Bittner, K. C., Romani, S., Magee, J. C. 2017; 20 (3): 417-426


    Place cells in the CA1 region of the hippocampus express location-specific firing despite receiving a steady barrage of heterogeneously tuned excitatory inputs that should compromise output dynamic range and timing. We examined the role of synaptic inhibition in countering the deleterious effects of off-target excitation. Intracellular recordings in behaving mice demonstrate that bimodal excitation drives place cells, while unimodal excitation drives weaker or no spatial tuning in interneurons. Optogenetic hyperpolarization of interneurons had spatially uniform effects on place cell membrane potential dynamics, substantially reducing spatial selectivity. These data and a computational model suggest that spatially uniform inhibitory conductance enhances rate coding in place cells by suppressing out-of-field excitation and by limiting dendritic amplification. Similarly, we observed that inhibitory suppression of phasic noise generated by out-of-field excitation enhances temporal coding by expanding the range of theta phase precession. Thus, spatially uniform inhibition allows proficient and flexible coding in hippocampal CA1 by suppressing heterogeneously tuned excitation.

    View details for DOI 10.1038/nn.4486

    View details for PubMedID 28114296

  • Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight. Neuron Milstein, A. D., Soltesz, I. 2017; 95 (4): 732–34


    The impact of dentate mossy cells on hippocampal activity remained uncertain despite a long history of investigation. In this issue of Neuron, Hashimotodani et al. (2017) discover a presynaptically expressed form of long-term potentiation at mossy cell outputs, shedding light on their mysterious function.

    View details for PubMedID 28817795

  • Behavioral time scale synaptic plasticity underlies CA1 place fields. Science (New York, N.Y.) Bittner, K. C., Milstein, A. D., Grienberger, C., Romani, S., Magee, J. C. 2017; 357 (6355): 1033–36


    Learning is primarily mediated by activity-dependent modifications of synaptic strength within neuronal circuits. We discovered that place fields in hippocampal area CA1 are produced by a synaptic potentiation notably different from Hebbian plasticity. Place fields could be produced in vivo in a single trial by potentiation of input that arrived seconds before and after complex spiking. The potentiated synaptic input was not initially coincident with action potentials or depolarization. This rule, named behavioral time scale synaptic plasticity, abruptly modifies inputs that were neither causal nor close in time to postsynaptic activation. In slices, five pairings of subthreshold presynaptic activity and calcium (Ca(2+)) plateau potentials produced a large potentiation with an asymmetric seconds-long time course. This plasticity efficiently stores entire behavioral sequences within synaptic weights to produce predictive place cell activity.

    View details for PubMedID 28883072

  • Axonal Filtering Allows Reliable Output during Dendritic Plateau-Driven Complex Spiking in CA1 Neurons NEURON Apostolides, P. F., Milstein, A. D., Grienberger, C., Bittner, K. C., Magee, J. C. 2016; 89 (4): 770-783


    In CA1 pyramidal neurons, correlated inputs trigger dendritic plateau potentials that drive neuronal plasticity and firing rate modulation. Given the strong electrotonic coupling between soma and axon, the >25 mV depolarization associated with the plateau could propagate through the axon to influence action potential initiation, propagation, and neurotransmitter release. We examined this issue in brain slices, awake mice, and a computational model. Despite profoundly inactivating somatic and proximal axon Na(+) channels, plateaus evoked action potentials that recovered to full amplitude in the distal axon (>150 μm) and triggered neurotransmitter release similar to regular spiking. This effect was due to strong attenuation of plateau depolarizations by axonal K(+) channels, allowing full axon repolarization and Na(+) channel deinactivation. High-pass filtering of dendritic plateaus by axonal K(+) channels should thus enable accurate transmission of gain-modulated firing rates, allowing neuronal firing to be efficiently read out by downstream regions as a simple rate code.

    View details for DOI 10.1016/j.neuron.2015.12.040

    View details for Web of Science ID 000373565200012

    View details for PubMedID 26833135

  • Inhibitory Gating of Input Comparison in the CA1 Microcircuit NEURON Milstein, A. D., Bloss, E. B., Apostolides, P. F., Vaidya, S. P., Dilly, G. A., Zemelman, B. V., Magee, J. C. 2015; 87 (6): 1274-1289


    Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

    View details for DOI 10.1016/j.neuron.2015.08.025

    View details for Web of Science ID 000363782200016

    View details for PubMedID 26402609

  • Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons NATURE NEUROSCIENCE Bittner, K. C., Grienberger, C., Vaidya, S. P., Milstein, A. D., Macklin, J. J., Suh, J., Tonegawa, S., Magee, J. C. 2015; 18 (8): 1133-?


    Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.

    View details for DOI 10.1038/nn.4062

    View details for Web of Science ID 000358605400015

    View details for PubMedID 26167906

    View details for PubMedCentralID PMC4888374

  • Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shi, Y., Suh, Y. H., Milstein, A. D., Isozaki, K., Schmid, S. M., Roche, K. W., Nicoll, R. A. 2010; 107 (37): 16315-16319


    Glutamate receptors of the AMPA subtype (AMPARs) mediate fast synaptic transmission in the brain. These ionotropic receptors rely on auxiliary subunits known as transmembrane AMPAR regulatory proteins (TARPs) for both trafficking and gating. Recently, a second family of AMPAR binding proteins, referred to as cornichons, were identified and also proposed to function as auxiliary subunits. Cornichons are transmembrane proteins that modulate AMPAR function in expression systems much like TARPs. In the present study we compare the role of cornichons in controlling AMPA receptor function in neurons and HEK cells to that of TARPs. Cornichons mimic some, but not all, of the actions of TARPs in HEK cells; their role in neurons, however, is more limited. Although expressed cornichons can affect the trafficking of AMPARs, they were not detected on the surface of neurons and failed to alter the kinetics of endogenous AMPARs. This neuronal role is more consistent with that of an endoplasmic reticulum (ER) chaperone rather than a bona fide auxiliary subunit.

    View details for DOI 10.1073/pnas.1011706107

    View details for Web of Science ID 000281799000062

    View details for PubMedID 20805473

  • TARP modulation of synaptic AMPA receptor trafficking and gating depends on multiple intracellular domains PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Milstein, A. D., Nicoll, R. A. 2009; 106 (27): 11348-11351


    Previous work has established stargazin and its related family of transmembrane AMPA receptor regulatory proteins (TARPs) as auxiliary subunits of AMPA receptors (AMPARs) that control synaptic strength both by targeting AMPARs to synapses through an intracellular PDZ-binding motif and by modulating their gating through an extracellular domain. However, TARPs gamma-2 and gamma-8 differentially regulate the synaptic targeting of AMPARs, despite having identical PDZ-binding motifs. Here, we investigate the structural elements that contribute to this functional difference between TARP subtypes by using domain transplantation and truncation. We identify a component of synaptic AMPAR trafficking that is independent of the TARP C-terminal PDZ-binding motif, and we establish previously uncharacterized roles for the TARP intracellular N terminus, loop, and C terminus in modulating both the trafficking and gating of synaptic AMPARs.

    View details for DOI 10.1073/pnas.0905570106

    View details for Web of Science ID 000267796100086

    View details for PubMedID 19549880

  • The Stoichiometry of AMPA Receptors and TARPs Varies by Neuronal Cell Type NEURON Shi, Y., Lu, W., Milstein, A. D., Nicoll, R. A. 2009; 62 (5): 633-640


    Synaptic AMPA receptors (AMPARs) are regulated by a family of auxiliary subunits known as transmembrane AMPA receptor regulatory proteins (TARPs). TARPs control the trafficking and gating of AMPARs. However, the number of TARP molecules that assemble within individual AMPAR channels is unknown. Here, we covalently link AMPARs to TARPs to investigate the properties of TARP/AMPAR complexes with known stoichiometry in HEK cells. We find that AMPARs are functional when associated with four, two, or no TARPs, and that the efficacy of the partial agonist kainate varies across these conditions, providing a sensitive assay for TARP/AMPAR stoichiometry. A comparison of these results with data obtained from hippocampal neurons demonstrates that native AMPARs associate with TARPs with a variable stoichiometry that depends on TARP expression level. Interestingly, AMPARs in hippocampal pyramidal neurons are saturated by TARP expression, while those in dentate gyrus granule neurons are not, indicating that variable TARP/AMPAR stoichiometry provides a mechanism for cell-type-specific regulation of AMPAR function.

    View details for DOI 10.1016/j.neuron.2009.05.016

    View details for Web of Science ID 000267119500006

    View details for PubMedID 19524523

  • Regulation of AMPA receptor gating and pharmacology by TARP auxiliary subunits TRENDS IN PHARMACOLOGICAL SCIENCES Milstein, A. D., Nicoll, R. A. 2008; 29 (7): 333-339


    Presynaptic glutamate release elicits brief waves of membrane depolarization in neurons by activating AMPA receptors. Depending on its precise size and shape, current through AMPA receptors gates downstream processes like NMDA receptor activation and action potential generation. Over a decade of research on AMPA receptor structure and function has identified binding sites on AMPA receptors for agonists, antagonists and allosteric modulators as well as key residues underlying differences in the gating behavior of various AMPA receptor subtypes. However, the recent discovery that AMPA receptors are accompanied in the synaptic membrane by a family of auxiliary subunits known as transmembrane AMPA receptor regulatory proteins (TARPs) has revealed that the kinetics and pharmacology of neuronal AMPA receptors differ in many respects from those predicted by classical studies of AMPA receptors in heterologous systems. Here, we summarize recent work and discuss remaining questions concerning the structure and function of native TARP-AMPA receptor complexes.

    View details for DOI 10.1016/

    View details for Web of Science ID 000257814700002

    View details for PubMedID 18514334

    View details for PubMedCentralID PMC2819157

  • Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels NATURE NEUROSCIENCE Bautista, D. M., Sigal, Y. M., Milstein, A. D., Garrison, J. L., Zorn, J. A., Tsuruda, P. R., NiColl, R. A., Julius, D. 2008; 11 (7): 772-779


    In traditional folk medicine, Xanthoxylum plants are referred to as 'toothache trees' because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Psychophysical studies have identified hydroxy-alpha-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns or other Xanthoxylum preparations. Although it is generally agreed that sanshool elicits its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate. Here we show that hydroxy-alpha-sanshool excites two types of sensory neurons, including small-diameter unmyelinated cells that respond to capsaicin (but not mustard oil) as well as large-diameter myelinated neurons that express the neurotrophin receptor TrkC. We found that hydroxy-alpha-sanshool excites neurons through a unique mechanism involving inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18), providing a framework for understanding the unique and complex psychophysical sensations associated with the Szechuan pepper experience.

    View details for DOI 10.1038/nn.2143

    View details for Web of Science ID 000257089400014

    View details for PubMedID 18568022

  • TARP subtypes differentially and dose-dependently control synaptic AMPA receptor Gating NEURON Milstein, A. D., Zhou, W., Karimzadegan, S., Bredt, D. S., Nicoll, R. A. 2007; 55 (6): 905-918


    A family of transmembrane AMPA receptor regulatory proteins (TARPs) profoundly affects the trafficking and gating of AMPA receptors (AMPARs). Although TARP subtypes are differentially expressed throughout the CNS, it is unclear whether this imparts functional diversity to AMPARs in distinct neuronal populations. Here, we examine the effects of each TARP subtype on the kinetics of AMPAR gating in heterologous cells and in neurons. We report a striking heterogeneity in the effects of TARP subtypes on AMPAR deactivation and desensitization, which we demonstrate controls the time course of synaptic transmission. In addition, we find that some TARP subtypes dramatically slow AMPAR activation kinetics. Synaptic AMPAR kinetics also depend on TARP expression level, suggesting a variable TARP/AMPAR stoichiometry. Analysis of quantal synaptic transmission in a TARP gamma-4 knockout (KO) mouse corroborates our expression data and demonstrates that TARP subtype-specific gating of AMPARs contributes to the kinetics of native AMPARs at central synapses.

    View details for DOI 10.1016/j.neuron.2007.08.022

    View details for Web of Science ID 000250078500008

    View details for PubMedID 17880894

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