Detrimental impacts of mixed-ion radiation on nervous system function.
Neurobiology of disease
Connecting Pathological Cellular Mechanisms to Large-Scale Seizure Structures.
Trends in neurosciences
Galactic cosmic radiation (GCR), composed of highly energetic and fully ionized atomic nuclei, can produce diverse deleterious effects on the body. In researching the neurological risks of GCR exposures, including during human spaceflight, various single-ion GCR irradiation paradigms have been shown to differentially disrupt cellular activity and overall behavior. However, it remains unclear how combined irradiation with a mix of multiple ions, more accurately recapitulating the space GCR environment, impacts the central nervous system. We therefore examined how mixed-ion GCR irradiation (containing combinations of protons, helium, oxygen, silicon and iron ions) influenced neuronal connectivity, functional generation of activity within neural circuits and cognitive behavior in mice. In electrophysiological recordings we find that space-relevant doses of mixed-ion GCR preferentially alter hippocampal inhibitory neurotransmission and produce related disruptions in the local field potentials of hippocampal oscillations. Such underlying perturbation in hippocampal network activity correspond to a range of deficits in cognitive tasks.
View details for DOI 10.1016/j.nbd.2021.105252
View details for PubMedID 33418069
Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy.
Epilepsy is a neurological disorder characterized by recurrent seizures, where abnormal electrical activity begins in a local brain area and propagates before terminating. In a recent study, Liou and colleagues used multiscale computational modeling to gain mechanistic insights into clinical seizure dynamics based on cellular-level biophysical properties.
View details for DOI 10.1016/j.tins.2020.04.006
View details for PubMedID 32376035
Transcriptional readout of neuronal activity via an engineered Ca2+-activated protease.
Proceedings of the National Academy of Sciences of the United States of America
Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by 50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.
View details for DOI 10.1667/RR15540.1
View details for PubMedID 32134362
Deep brain optogenetics without intracranial surgery.
Molecular integrators, in contrast to real-time indicators, convert transient cellular events into stable signals that can be exploited for imaging, selection, molecular characterization, or cellular manipulation. Many integrators, however, are designed as complex multicomponent circuits that have limited robustness, especially at high, low, or nonstoichiometric protein expression levels. Here, we report a simplified design of the calcium and light dual integrator FLARE. Single-chain FLARE (scFLARE) is a single polypeptide chain that incorporates a transcription factor, a LOV domain-caged protease cleavage site, and a calcium-activated TEV protease that we designed through structure-guided mutagenesis and screening. We show that scFLARE has greater dynamic range and robustness than first-generation FLARE and can be used in culture as well as in vivo to record patterns of neuronal activation with 10-min temporal resolution.
View details for DOI 10.1073/pnas.2006521117
View details for PubMedID 33323488
Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks
2019; 101 (6): 1016?28
The GABAA Receptor ? Subunit Is Required for Inhibitory Transmission.
2018; 98 (4): 718?25.e3
Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7?mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.
View details for DOI 10.1038/s41587-020-0679-9
View details for PubMedID 33020604
Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.
While the canonical assembly of a GABAA receptor contains two ? subunits, two ? subunits, and a fifth subunit, it is unclear which variants of each subunit are necessary for native receptors. We used CRISPR/Cas9 to dissect the role of the GABAA receptor ? subunits in inhibitory transmission onto hippocampal CA1 pyramidal cells and found that deletion of all ? subunits 1, 2, and 3 completely eliminated inhibitory responses. In addition, only knockout of ?3, alone or in combination with another ? subunit, impaired inhibitory synaptic transmission. We found that ?3 knockout impairs inhibitory input from PV but not SOM expressing interneurons. Furthermore, expression of ?3 alone on the background of the ?1-3 subunit knockout was sufficient to restore synaptic and extrasynaptic inhibitory transmission. These findings reveal a crucial role for the ?3 subunit in inhibitory transmission and identify a synapse-specific role of the ?3 subunit in GABAergic synaptic transmission.
View details for DOI 10.1016/j.neuron.2018.03.046
View details for PubMedID 29706582
View details for PubMedCentralID PMC6089239
Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.
Proceedings of the National Academy of Sciences of the United States of America
2015; 112 (8): 2551?56
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.
View details for DOI 10.7554/eLife.19236
View details for PubMedID 27805570
View details for PubMedCentralID PMC5098909
Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.
View details for DOI 10.1073/pnas.1500501112
View details for PubMedID 25675530
View details for PubMedCentralID PMC4345621