Faculty Opinions recommendation of Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo.

Abstract Background Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Cancers ◽

10.3390/cancers13143437 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3437

Author(s):

Hee Eun Kang ◽

Yoojeong Seo ◽

Jun Seop Yun ◽

Sang Hyun Song ◽

Dawool Han ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Target Gene ◽

Advanced Colorectal Cancer ◽

Therapeutic Potential ◽

Cancer Stemness ◽

Reciprocal Regulation ◽

Canonical Wnt

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

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Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

Journal of Alzheimer s Disease ◽

10.3233/jad-201174 ◽

2021 ◽

pp. 1-16

Author(s):

Masaki Nakano ◽

Yachiyo Mitsuishi ◽

Lei Liu ◽

Naoki Watanabe ◽

Emi Hibino ◽

...

Keyword(s):

Neuronal Activity ◽

Epithelial Mesenchymal Transition ◽

Surrogate Marker ◽

Amyloid Β ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Extracellular Release ◽

Activity Dependent ◽

Aβ Production

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

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The Prototoxin lynx1 Acts on Nicotinic Acetylcholine Receptors to Balance Neuronal Activity and Survival In Vivo

Neuron ◽

10.1016/j.neuron.2006.07.025 ◽

2006 ◽

Vol 51 (5) ◽

pp. 587-600 ◽

Cited By ~ 89

Author(s):

Julie M. Miwa ◽

Tanya R. Stevens ◽

Sarah L. King ◽

Barbara J. Caldarone ◽

Ines Ibanez-Tallon ◽

...

Keyword(s):

Neuronal Activity ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine

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In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis

Experimental & Molecular Medicine ◽

10.1038/emm.2013.89 ◽

2013 ◽

Vol 45 (10) ◽

pp. e46-e46 ◽

Cited By ~ 42

Author(s):

Su-Jin Moon ◽

Jin-Sil Park ◽

Yu-Jung Heo ◽

Chang-Min Kang ◽

Eun-Kyung Kim ◽

...

Keyword(s):

Treg Cells ◽

Collagen Induced Arthritis ◽

Reciprocal Regulation

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Fiber photometry does not reflect spiking activity in the striatum

10.1101/2021.01.20.427525 ◽

2021 ◽

Author(s):

Alex A. Legaria ◽

Julia A. Licholai ◽

Alexxai V. Kravitz

Keyword(s):

Neuronal Activity ◽

Calcium Imaging ◽

Brain Activity ◽

Neural Population ◽

Fluorescence Signal ◽

Calcium Signals ◽

Cellular Events ◽

Neural Populations ◽

Spiking Activity

AbstractFiber photometry recordings are commonly used as a proxy for neuronal activity, based on the assumption that increases in bulk calcium fluorescence reflect increases in spiking of the underlying neural population. However, this assumption has not been adequately tested. Here, using endoscopic calcium imaging in the striatum we report that the bulk fluorescence signal correlates weakly with somatic calcium signals, suggesting that this signal does not reflect spiking activity, but may instead reflect subthreshold changes in neuropil calcium. Consistent with this suggestion, the bulk fluorescence photometry signal correlated strongly with neuropil calcium signals extracted from these same endoscopic recordings. We further confirmed that photometry did not reflect striatal spiking activity with simultaneous in vivo extracellular electrophysiology and fiber photometry recordings in awake behaving mice. We conclude that the fiber photometry signal should not be considered a proxy for spiking activity in neural populations in the striatum.Significance statementFiber photometry is a technique for recording brain activity that has gained popularity in recent years due to it being an efficient and robust way to record the activity of genetically defined populations of neurons. However, it remains unclear what cellular events are reflected in the photometry signal. While it is often assumed that the photometry signal reflects changes in spiking of the underlying cell population, this has not been adequately tested. Here, we processed calcium imaging recordings to extract both somatic and non-somatic components of the imaging field, as well as a photometry signal from the whole field. Surprisingly, we found that the photometry signal correlated much more strongly with the non-somatic than the somatic signals. This suggests that the photometry signal most strongly reflects subthreshold changes in calcium, and not spiking. We confirmed this point with simultaneous fiber photometry and extracellular spiking recordings, again finding that photometry signals relate poorly to spiking in the striatum. Our results may change interpretations of studies that use fiber photometry as an index of spiking output of neural populations.

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Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

10.1101/2020.06.09.141556 ◽

2020 ◽

Author(s):

Jelena Scekic-Zahirovic ◽

Inmaculada Sanjuan-Ruiz ◽

Vanessa Kan ◽

Salim Megat ◽

Pierre De Rossi ◽

...

Keyword(s):

Neuronal Activity ◽

Rna Binding ◽

Gene Mutations ◽

Neuronal Loss ◽

Inhibitory Neurons ◽

Inhibitory Synapses ◽

Behavioral Alterations ◽

Behavioral Abnormalities ◽

Cytoplasmic Accumulation

AbstractGene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

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Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2020810118 ◽

2020 ◽

Vol 118 (1) ◽

pp. e2020810118

Author(s):

Ye Wang ◽

Wing-Yu Fu ◽

Kit Cheung ◽

Kwok-Wang Hung ◽

Congping Chen ◽

...

Keyword(s):

Synaptic Plasticity ◽

Neuronal Activity ◽

Hippocampal Slices ◽

Memory Formation ◽

Conditional Knockout ◽

Acute Administration ◽

Excitatory Synapses ◽

Homeostatic Synaptic Plasticity ◽

Hippocampal Ca1

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

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