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.

Long-Term-But Not Short-Term-Plasticity at the Mossy Fiber-CA3 Pyramidal Cell Synapse in Hippocampus Is Altered in M1/M3 Muscarinic Acetylcholine Receptor Double Knockout Mice.

Muscarinic acetylcholine receptors are well-known for their crucial involvement in hippocampus-dependent learning and memory, but the exact roles of the various receptor subtypes (M1-M5) are still not fully understood. Here, we studied how M1 and M3 receptors affect plasticity at the mossy fiber (MF)-CA3 pyramidal cell synapse. In hippocampal slices from M1/M3 receptor double knockout (M1/M3-dKO) mice, the signature short-term plasticity of the MF-CA3 synapse was not significantly affected.

2D-dwell-time analysis with simulations of ion-channel gating using high-performance computing.

Single-channel patch-clamp recordings allow observing the action of a single protein complex in real time and hence the deduction of the underlying conformational changes in the ion-channel protein. Commonly, recordings are modeled using hidden Markov chains, connecting open and closed states in the experimental data with protein conformations. The rates between states denote transition probabilities that could be modified by membrane voltage or ligand binding.

Mechanical behavior of the hippocampus and corpus callosum: An attempt to reconcile ex vivo with in vivo and micro with macro properties.

Mechanical properties of brain tissue are very complex and vary with the species, region, method, and dynamic range, and between in vivo and ex vivo measurements. To reconcile this variability, we investigated in vivo and ex vivo stiffness properties of two distinct regions in the human and mouse brain - the hippocampus (HP) and the corpus callosum (CC) - using different methods. Under quasi-static conditions, we examined ex vivo murine HP and CC by atomic force microscopy (AFM).

Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies.

Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells.

Activin A, a member of the TGF-β family, is recognized as a multifunctional protein in the adult brain with a particular impact on neuronal circuits associated with cognitive and affective functions. Activin receptor signaling in mouse hippocampus is strongly enhanced by the exploration of an enriched environment (EE), a behavioral paradigm known to improve performance in learning and memory tasks and to ameliorate depression-like behaviors. To interrogate the relationship between EE, activin signaling, and cellular excitability in the hippocampus, we performed whole-cell recordings from dentate gyrus (DG) granule cells (GCs) of wild type mice and transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), which disrupts activin signaling in a forebrain-specific fashion.

Astrogenesis in the murine dentate gyrus is a life-long and dynamic process.

Astrocytes are highly abundant in the mammalian brain, and their functions are of vital importance for all aspects of development, adaption, and aging of the central nervous system (CNS). Mounting evidence indicates the important contributions of astrocytes to a wide range of neuropathies. Still, our understanding of astrocyte development significantly lags behind that of other CNS cells.

Environmental enrichment recruits activin A to recalibrate neural activity in mouse hippocampus.

The TGF-β family member activin A modulates neural underpinnings of cognitive and affective functions in an activity-dependent fashion. We have previously shown that exploration of a novel and enriched environment (EE) strongly enhanced activin signaling. Whereas the many beneficial effects of EE are amply documented, the underlying mechanisms remain largely elusive.

Excitatory Effects of Calcitonin Gene-Related Peptide (CGRP) on Superficial Sp5C Neurons in Mouse Medullary Slices.

The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices.

Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability.

The acid sphingomyelinase (ASM) converts sphingomyelin into ceramide. Recent work has advanced the ASM/ceramide system as a major player in the pathogenesis of major depressive disorder (MDD). Indeed, ASM activity is enhanced in MDD patients and antidepressant drugs like fluoxetine act as functional inhibitors of ASM.

Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission.

The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the postsynaptic scaffolding protein gephyrin.

Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats.

Background: The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.

Sox11 is an Activity-Regulated Gene with Dentate-Gyrus-Specific Expression Upon General Neural Activation.

Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood.

Muscarinic Modulation of Morphologically Identified Glycinergic Neurons in the Mouse PreBötzinger Complex.

The cholinergic system plays an essential role in central respiratory control, but the underlying mechanisms remain elusive. We used whole-cell recordings in brainstem slices from juvenile mice expressing enhanced green fluorescent protein (EGFP) under the control of the glycine transporter type 2 (GlyT) promoter, to examine muscarinic modulation of morphologically identified glycinergic neurons in the preBötzinger complex (preBötC), an area critical for central inspiratory rhythm generation. Biocytin-filled reconstruction of glycinergic neurons revealed that the majority of them had few primary dendrites and had axons arborized within their own dendritic field.

Swiprosin1/EFhd2 is involved in the monoaminergic and locomotor responses of psychostimulant drugs.

Psychostimulants are widely abused drugs that may cause addiction in vulnerable individuals. While the reward circuitry of the brain is involved in addiction establishment, various pathways in the brain may provide protection at the molecular level that limits the acute and chronic effects of drugs. These targets may be used for strategies designed to prevent and treat addiction.

β-Secretase BACE1 Is Required for Normal Cochlear Function.

Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1 mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs).

Chronic antipsychotic treatment targets GIRK current suppression, loss of long-term synaptic depression and behavioural sensitization in a mouse model of amphetamine psychosis.

Background:: Antipsychotic drugs (APDs) are the mainstay of the pharmacological treatment of psychotic disorders like schizophrenia. While the clinical efficacy of APDs has long since been established, the neurobiological mechanisms underlying their therapeutic benefits are still not well understood.

Methods:: Here, we used an escalating amphetamine regimen to induce a psychosis-like state in mice.

Doxorubicin induces caspase-mediated proteolysis of KV7.1.

K7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac I channel. Gain- and loss-of-function mutations in are associated with cardiac arrhthymias, highlighting the importance of modulating I activity for cardiac function.