Richard Kramer
VerifiedUniversity of California, Berkeley · Neuroscience
Active 1907–2025
About
Richard Kramer is a Professor of Neuroscience at the University of California, Berkeley. His research interests include the development and application of novel chemical reagents for non-invasive optical sensing and manipulation of ion channels and synapses. He is a faculty member within the Neuroscience Department, contributing to the understanding of molecular and cellular neuroscience. His contact information includes an email address (rhkramer@berkeley.edu), a phone number (510-643-2406), and an office located at 121A Weill Hall. His work focuses on advancing techniques for studying neural function through innovative chemical tools, supporting the broader goals of neuroscience research at Berkeley.
Research topics
- Neuroscience
- Chemistry
- Medicine
- Biophysics
- Ophthalmology
Selected publications
British Journal of Pharmacology · 2025-09-28
articleOpen accessBACKGROUND AND PURPOSE: The functional organization of corneal cold nerve endings, critical structures in maintaining the ocular surface, remains poorly understood. Here, the photoisomerizable small-molecule diethylamine-azobenzene-quaternary ammonium (DENAQ) was used to photomodulate activity of cold-sensing nerve terminals in control and chronic tear-deficient corneas. Furthermore, DENAQ was used for in vivo photochemical regulation of the thermally induced blink reflex. EXPERIMENTAL APPROACH: Extracellular nerve terminal impulse activity was recorded on cold terminals in excised corneas of naïve and tear-deficient guinea pigs pre-incubated with DENAQ. Pulses of light at a wavelength of 460 nm were delivered to the perfused corneas. The thermally induced blink reflex was assessed using orbicularis oculi electromyography in anaesthetised rats after topical administration of DENAQ to the eye under blue light and darkness conditions. KEY RESULTS: Exposure to blue light robustly reduced spontaneous activity of both naïve and tear-deficient cold nerve terminals pre-incubated with DENAQ, while cold-evoked responses remained unaffected. Pre-incubation of excised corneas with DENAQ, along with pharmacological P2X receptor antagonists, prevented the DENAQ-mediated photoreduction of the cold nerve terminal spontaneous activity. In addition, blue light increased cold-evoked reflex blink in eyes pre-treated with DENAQ. CONCLUSION AND IMPLICATIONS: ) channel activity. Furthermore, the cold-evoked blink reflex is modulated by light in DENAQ-treated eyes. Chemical photoswitches like DENAQ might be potential new treatments for ocular discomfort and pain in dry eye disease.
Author response: A toolbox for ablating excitatory and inhibitory synapses
2025-03-13
peer-reviewOpen accessRecombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Research Square · 2025-11-17 · 1 citations
preprintOpen accessAuthor response: A toolbox for ablating excitatory and inhibitory synapses
2025-04-29
peer-reviewOpen accessWithin the brain are circuits of neurons that communicate with one another via junctions known as synapses. The pre-synaptic neuron, which sends the signal, releases proteins known as neurotransmitters into the synapse which then bind to receptors on the receiving, or postsynaptic, neuron. If the receptors at the synapse are excitatory, they increase the chances of the postsynaptic neuron ‘firing’ and propagating the signal. In contrast, if the receptors are inhibitory, this reduces the likelihood of the neuron firing, dampening communication across the circuit. In a previous study, a tool known as GFE3 was developed that can specifically eliminate inhibitory synapses by binding to scaffolding proteins called gephyrins that anchor inhibitory receptors in place. Attached to GFE3 is an enzyme that triggers gephyrin degradation, leading to the dismantling of the synapse and blocking of the inhibitory signal. The tool has been used to study various behaviors, including how mice control their rhythmic whisker movements and vocalization patterns. Bareghamyan et al. – who are part of the research group that carried out the previous work – have now refined GFE3 so it can be activated more precisely and controllably. The team produced two new versions: one that is activated by light, and another that is activated by a cell-permeable chemical compound known as trimethoprim-Halotag ligand. In addition, Bareghamyan et al. engineered a new tool called PFE3 which is designed to eliminate excitatory synapses. PFE3 targets PSD-95, the predominant scaffold protein found in excitatory synapses. It also contains two enzymes that work together to degrade PSD-95, leading to a loss of excitatory receptors. Further experiments showed that PFE3 efficiently reduced the number of excitatory synapses in rat neurons cultured in a dish as well as in neurons found in the retinas of mice. The synapse ablators developed by Bareghamyan et al. offer a fast, efficient and reversible approach for eliminating both excitatory and inhibitory synapses. These tools will make it easier for neuroscientists to silence specific postsynaptic neurons and expand the toolkit available for manipulating and studying neuronal circuits.
A toolbox for ablating excitatory and inhibitory synapses
eLife · 2025-04-29
articleOpen accessRecombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
A toolbox for ablating excitatory and inhibitory synapses
eLife · 2025-03-13
preprintOpen accessAbstract Recombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Journal of Neuroscience · 2024-05-22 · 5 citations
articleOpen accessMagnetogenetics was developed to remotely control genetically targeted neurons. A variant of magnetogenetics uses magnetic fields to activate transient receptor potential vanilloid (TRPV) channels when coupled with ferritin. Stimulation with static or RF magnetic fields of neurons expressing these channels induces Ca 2+ transients and modulates behavior. However, the validity of ferritin-based magnetogenetics has been questioned due to controversies surrounding the underlying mechanisms and deficits in reproducibility. Here, we validated the magnetogenetic approach Ferritin-iron Redistribution to Ion Channels (FeRIC) using electrophysiological (Ephys) and imaging techniques. Previously, interference from RF stimulation rendered patch-clamp recordings inaccessible for magnetogenetics. We solved this limitation for FeRIC, and we studied the bioelectrical properties of neurons expressing TRPV4 (nonselective cation channel) and transmembrane member 16A (TMEM16A; chloride-permeable channel) coupled to ferritin (FeRIC channels) under RF stimulation. We used cultured neurons obtained from the rat hippocampus of either sex. We show that RF decreases the membrane resistance (Rm) and depolarizes the membrane potential in neurons expressing TRPV4 FeRIC . RF does not directly trigger action potential firing but increases the neuronal basal spiking frequency. In neurons expressing TMEM16A FeRIC , RF decreases the Rm, hyperpolarizes the membrane potential, and decreases the spiking frequency. Additionally, we corroborated the previously described biochemical mechanism responsible for RF-induced activation of ferritin-coupled ion channels. We solved an enduring problem for ferritin-based magnetogenetics, obtaining direct Ephys evidence of RF-induced activation of ferritin-coupled ion channels. We found that RF does not yield instantaneous changes in neuronal membrane potentials. Instead, RF produces responses that are long-lasting and moderate, but effective in controlling the bioelectrical properties of neurons.
A toolbox for ablating excitatory and inhibitory synapses
eLife · 2024-12-06
preprintOpen accessAbstract Recombinant optogenetic and chemogenetic proteins that manipulate neuronal activity are potent tools for activating and inhibiting neuronal circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer, HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Journal of Neuroscience · 2024-07-26 · 3 citations
articleOpen accessSenior authorIn retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel has remained unknown. Here we report that synaptic output from BCs plummets in RP mouse models of both sexes owing to loss of voltage-gated Ca 2+ channels. Remodeling reduces the reliability of synaptic output to repeated optogenetic stimuli, causing RGC firing to fail at high-stimulus frequencies. Fortunately, functional remodeling of BCs can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated either by surviving photoreceptors or by vision-restoring tools.
A toolbox for ablating excitatory and inhibitory synapses
bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-24
preprintOpen accessRecombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Recent grants
A universal photoswitch system for optical control of neuronal receptors
NIH · $1.2M · 2009–2013
Light-activated ion chanenls for remote control of neuronal activity
NIH · $1.6M · 2008–2013
Optical studies of the cone photoreceptor synapse
NIH · $3.9M · 2004–2015
Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior
NIH · $2.4M · 2014–2017
NIH · $880k · 2003
Frequent coauthors
- 51 shared
Dirk Trauner
- 39 shared
Alexandre Mourot
Laboratoire Plasticité du Cerveau
- 29 shared
Ivan Tochitsky
Harvard University
- 23 shared
Ehud Y. Isacoff
- 19 shared
Karl Šafář
- 16 shared
Maximilian Salzmann
Hôpital Femme Mère Enfant
- 15 shared
Matthew R. Banghart
University of California, San Diego
- 13 shared
K. Stargardt
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