About

Ehud Isacoff is a Professor of Neuroscience and holds the Evan Rauch Chair in Neuroscience at the University of California, Berkeley. He is part of the Department of Molecular and Cell Biology, Neuroscience division. His research interests include mechanisms of ion channel function, synapse development, plasticity, and neural circuit function. As a faculty member, he contributes to the understanding of fundamental processes in neuroscience, focusing on how neural circuits develop and adapt through molecular and cellular mechanisms.

Research topics

• Chemistry
• Biophysics
• Biology
• Neuroscience
• Cell biology

Selected publications

• Red-Shifted Chemigenetic Glutamate Indicators for Recording Multiplexed Neural Computation

  SSRN Electronic Journal · 2026-01-01

  preprintOpen access
  PublisherDOI

• Dopamine D1 receptor activation in the striatum is sufficient to drive reinforcement of anteceding cortical patterns

  Neuron · 2025-01-14 · 11 citations

  articleOpen accessSenior author

  Timed dopamine signals underlie reinforcement learning, favoring neural activity patterns that drive behaviors with positive outcomes. In the striatum, dopamine activates five dopamine receptors (D1R-D5R), which are differentially expressed in striatal neurons. However, the role of specific dopamine receptors in reinforcement is poorly understood. Using our cell-specific D1R photo-agonist, we find that D1R activation in D1-expressing neurons in the dorsomedial striatum is sufficient to reinforce preceding neural firing patterns in defined ensembles of layer 5 cortico-striatal neurons of the mouse motor cortex. The reinforcement is cumulative and time dependent, with an optimal effect when D1R activation follows the selected neural pattern after a short interval. Our results show that D1R activation in striatal neurons can selectively reinforce cortical activity patterns, independent of a behavioral outcome or a reward, crucially contributing to the fundamental mechanisms that support cognitive functions like learning, memory, and decision-making.

  PublisherDOI

• Balanced synapse-to-synapse short-term plasticity ensures constant transmitter release

  Current Biology · 2025-06-01 · 4 citations

  articleOpen accessSenior author

  Synaptic strength can vary greatly between synapses. Optical quantal analysis at Drosophila glutamatergic motor neuron synapses shows that short-term plasticity also varies greatly between synapses, even those made by an individual motor neuron. Strong and weak synapses are randomly distributed in the motor neuron nerve terminal, as are facilitating and depressing synapses. Although synapses exhibit highly heterogeneous basal strength at low-action potential firing frequency and undergo varied plasticity when firing frequency increases, the overall distribution of strength across synapses remains remarkably constant due to a balance between the number of synapses that facilitate versus depress and to their degree of plasticity and basal synaptic weight. Constancy in transmitter release can ensure robustness across changing behavioral conditions.

  PublisherOA PDFDOI

• Domain coupling in activation of a family C GPCR

  Nature Chemical Biology · 2025-04-25 · 3 citations

  articleOpen accessSenior author

  The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological functions. We employ molecular dynamics, single-molecule spectroscopy and hydrogen-deuterium exchange to dissect the activation pathway triggered by glutamate. We find that activation entails multiple loosely coupled steps, including formation of an agonist-bound, pre-active intermediate whose transition to active conformations forms dimerization interface contacts that set efficacy. The agonist-bound receptor populates at least two additional intermediates en route to G protein-coupling conformations. Sequential transitions into these states act as 'gates', which attenuate the effects of glutamate. Thus, the agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation by allosteric ligands. Sequence variation within the dimerization interface, as well as altered conformational coupling in receptor heterodimers, may contribute to precise decoding of glutamate signals over broad spatial and temporal scales.

  PublisherOA PDFDOI

• Behavioral resilience via dynamic circuit firing homeostasis

  Proceedings of the National Academy of Sciences · 2025-04-29 · 2 citations

  articleOpen accessSenior authorCorresponding

  larvae, either presynaptic weakening due to perturbation of transmitter release or postsynaptic weakening due to perturbation of glutamate receptors at synapses between motor neuron (MN) and muscle has little impact on locomotion, suggesting a nonsynaptic compensatory mechanism. In vivo imaging shows that five different forms of synaptic weakening increase the duration of activity bouts in type I MNs. Strikingly, this compensation is input selective: occurring only in the tonic type Ib MN, not the phasic type Is MN that innervates the same muscle. Moreover, an inhibitory class of central pre-MNs that innervates the tonic-but not phasic-input decreases in activity. The adjustment in activity occurs remarkably quickly: within minutes of synapse perturbation. We propose that MN firing is dynamically regulated by two coordinated mechanisms: a cell-autonomous adjustment of MN excitability and a circuit adjustment of inhibitory central drive. The input selectivity of this process suggests homeostatic adjustment to maintain tonic drive but hold constant the phasic drive that organizes locomotory wave patterns.

  PublisherOA PDFDOI

• Deficiency in transmitter release triggers homeostatic transcriptional changes that increase presynaptic excitability

  Proceedings of the National Academy of Sciences · 2025-07-29 · 1 citations

  articleOpen accessSenior authorCorresponding

  Weakening of synaptic transmission at the Drosophila larval neuromuscular junction triggers two forms of homeostatic compensation, one that increases the probability of glutamate release per action potential ( P r ) and another that increases motoneuron (MN) activity. We investigated the molecular changes in MNs that underlie the increase in MN activity. RNA sequencing (RNA-seq) analysis on MNs whose glutamate release is weakened by knockdown of components of the MN transmitter release machinery reveals a reduction in expression of a group of genes that encode potassium channels and their positive modulators. These results identify a mechanism of compensation for weakened synaptic transmission by MNs, which engages a transcriptional program in those cells to increase firing and, thereby, ensure sufficient locomotory drive.

  PublisherOA PDFDOI

• Reversible Antagonism of Dopamine D1 Receptor Using a Photoswitchable Remotely Tethered Ligand

  ACS Chemical Biology · 2025-10-16

  articleCorresponding

  Dopamine D1 receptor (D1R) plays key roles in health and disease. D1R is broadly expressed throughout the brain and body and is dynamically activated in response to endogenous dopamine, making it difficult to target this receptor with sufficient precision. We previously developed a robust light-activatable, tetherable agonist for D1R, wherein a temporally precise photoswitch (the P compound) binds to a genetically encoded membrane anchoring protein (the M protein) in specific brain locations and cell types. Here we extended our approach by developing a complementary antagonist P compound that could be used to block specific populations of D1R in the brain with precise timing. Together, we have generated a robust toolkit for interrogating D1R function in the brain with unprecedented precision.

  PublisherDOI

• Reversible Antagonism of Dopamine D1 Receptor using a Photoswitchable Remotely Tethered Ligand

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-15

  preprintOpen accessCorresponding

  Dopamine D1 receptor (D1R) plays key roles in health and disease. D1R is broadly expressed throughout the brain and body and is dynamically activated in response to endogenous dopamine, making it difficult to target this receptor with sufficient precision. We previously developed a robust light-activatable, tetherable agonist for D1R, wherein a temporally precise photo-switch (the P compound) binds to a genetically-encoded membrane anchoring protein (the M protein) in specific brain locations and cell types. Here we extended our approach by developing a complementary antagonist P compound that could be used to block specific populations of D1R in the brain with precise timing. Together, we have generated a robust toolkit for interrogating D1R function in the brain with unprecedented precision.

  PublisherOA PDFDOI

• Structure and dynamics determine G protein coupling specificity at a class A GPCR

  Science Advances · 2025-03-19 · 33 citations

  articleOpen access

  G protein–coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR–G protein complexes, little is known about the mechanism of G protein coupling specificity. The β 2 -adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

  PublisherDOI

• Frequency-multiplexed aberration measurement for confocal microscopy

  Optics Express · 2024-07-16 · 5 citations

  articleOpen access

  In single-photon confocal fluorescence microscopy, optical aberration affects both excitation and detection light paths, thus can severely degrade image quality. We incorporated an adaptive optics (AO) module into a confocal microscope and used a frequency-multiplexed aberration measurement method to measure and correct sample-induced aberration. We demonstrated that this method can measure aberration using signals from features of different sizes and recover diffraction-limited imaging performance. Applying our AO confocal microscope to imaging through and within living zebrafish larvae, as well as in the mouse brain in vivo, we showed that aberration correction can substantially improve confocal image brightness, resolution, and contrast.

  PublisherDOI

Recent grants

• NIH Grant R01NS035549

  NIH · $5.1M · 2015

• Synaptic to circuit homeostasis in the Drosophila locomotor system

  NIH · $1.6M · 2019–2024

• NIH Grant S10RR02897101A1

  NIH · $596k · 2012

• BRAIN EAGER: Analysis of brain circuits with optically controlled synaptic GPCRs

  NSF · $300k · 2014–2016

• Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior

  NIH · $2.4M · 2014–2017

Frequent coauthors

• Dirk Trauner

  107 shared

• Lily Yeh Jan

  University of California, San Francisco

  72 shared

• Yuh Nung Jan

  University of California, San Francisco

  67 shared

• Joshua Levitz

  Cornell University

  50 shared

• Daniel L. Minor

  University of California, San Francisco

  40 shared

• Andreas Reiner

  Ruhr University Bochum

  39 shared

• Maximilian H. Ulbrich

  University of Freiburg

  39 shared

• Guillaume Sandoz

  Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique

  38 shared

Education

• PhD, Physiology

  McGill University

  1988

• BSc, Biology

  McGill University

  1981