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1.
Neuron ; 111(10): 1547-1563.e9, 2023 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-37015225

RESUMO

The ability to optically image cellular transmembrane voltages at millisecond-timescale resolutions can offer unprecedented insight into the function of living brains in behaving animals. Here, we present a point mutation that increases the sensitivity of Ace2 opsin-based voltage indicators. We use the mutation to develop Voltron2, an improved chemigeneic voltage indicator that has a 65% higher sensitivity to single APs and 3-fold higher sensitivity to subthreshold potentials than Voltron. Voltron2 retained the sub-millisecond kinetics and photostability of its predecessor, although with lower baseline fluorescence. In multiple in vitro and in vivo comparisons with its predecessor across multiple species, we found Voltron2 to be more sensitive to APs and subthreshold fluctuations. Finally, we used Voltron2 to study and evaluate the possible mechanisms of interneuron synchronization in the mouse hippocampus. Overall, we have discovered a generalizable mutation that significantly increases the sensitivity of Ace2 rhodopsin-based sensors, improving their voltage reporting capability.


Assuntos
Enzima de Conversão de Angiotensina 2 , Rodopsina , Camundongos , Animais , Potenciais de Ação/fisiologia , Rodopsina/genética , Neurônios/fisiologia , Mutação/genética
2.
Cell Rep ; 21(8): 2104-2117, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29166603

RESUMO

Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the CNS, Th17 lymphocytes cross the blood-brain barrier (BBB) before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.


Assuntos
Barreira Hematoencefálica/metabolismo , Caveolina 1/metabolismo , Inflamação/metabolismo , Células Th1/imunologia , Junções Íntimas/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Endotélio Vascular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Células Th17/imunologia
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