A deep learning approach to real-time Markov modeling of ion channel gating.

The patch-clamp technique allows us to eavesdrop the gating behavior of individual ion channels with unprecedented temporal resolution. The signals arise from conformational changes of the channel protein as it makes rapid transitions between conducting and non-conducting states. However, unambiguous analysis of single-channel datasets is challenging given the inadvertently low signal-to-noise ratio as well as signal distortions caused by low-pass filtering.

Multicolor, Cell-Impermeable, and High Affinity BACE1 Inhibitor Probes Enable Superior Endogenous Staining and Imaging of Single Molecules.

The prevailing but not undisputed amyloid cascade hypothesis places the β-site of APP cleaving enzyme 1 (BACE1) center stage in Alzheimer's Disease pathogenesis. Here, we investigated functional properties of BACE1 with novel tag- and antibody-free labeling tools, which are conjugates of the BACE1-inhibitor IV (also referred to as C3) linked to different impermeable Alexa Fluor dyes. We show that these fluorescent small molecules bind specifically to BACE1, with a 1:1 labeling stoichiometry at their orthosteric site.

Increase in activin A may counteract decline in synaptic plasticity with age.

Activin A, a member of the transforming growth factor β (TGF-β) family, is widely recognized for its neurotrophic and neuroprotective function in the developing and injured brain, respectively. Moreover, in the healthy adult brain, activin A has been shown to tune signal processing at excitatory synapses in a fashion that improves cognitive performance. Because its level in human cerebrospinal fluid rises with age, we wondered whether activin A has a role in mitigating the gradual cognitive decline that healthy individuals experience in late-life.

Tonic activin signaling shapes cellular and synaptic properties of CA1 neurons mainly in dorsal hippocampus.

Dorsal and ventral hippocampus serve different functions in cognition and affective behavior, but the underpinnings of this diversity at the cellular and synaptic level are not well understood. We found that the basal level of activin A, a member of the TGF-β family, which regulates hippocampal circuits in a behaviorally relevant fashion, is much higher in dorsal than in ventral hippocampus. Using transgenic mice with a forebrain-specific disruption of activin receptor signaling, we identified the pronounced dorsal-ventral gradient of activin A as a major factor determining the distinct neurophysiologic signatures of dorsal and ventral hippocampus, ranging from pyramidal cell firing, tuning of frequency-dependent synaptic facilitation, to long-term potentiation (LTP), long-term depression (LTD), and de-potentiation.

Dorsal-Ventral Gradient of Activin Regulates Strength of GABAergic Inhibition along Longitudinal Axis of Mouse Hippocampus in an Activity-Dependent Fashion.

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this difference is effected by the dorsal-ventral gradient of activin A, a member of the transforming growth factor-β family, which is increasingly recognized for its modulatory role in brain regions involved in cognitive functions and affective behavior.