Synaptic dysfunction caused by truncated tau is associated with hyperpolarization-activated cyclic nucleotide-gated channelopathy

Neurodegenerative tauopathies are characterized by deposition in the brain of highly phosphorylated and truncated forms of tau, but how these impact on cellular processes remains unknown. Here, we show that hyperpolarization-induced membrane voltage ‘sag’, which is dependent on hyperpolarization-activated inward-rectifying (Ih) current and hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, is increased in the Tau35 mouse model of human tauopathy. Expression of Tau35, corresponding to a fragment comprising the carboxy-terminal half of tau first identified in human tauopathy brain, reduces dendritic branching in mouse brain and in cultured hippocampal neurons, and decreases synaptic density. Neuronal expression of Tau35 results in increased tau phosphorylation and significant disruption to synaptic ultrastructure, including marked and progressive reductions in synaptic vesicle counts and vesicle cluster density. Ultrastructural analysis reveals that the positioning of synaptic vesicles is perturbed by Tau35, causing vesicles to accumulate at sites adjacent to the active zone and at the lateral edges of the cluster. These structural changes induced by Tau35 correlate with functional abnormalities in network activity, including increased width, reduced frequency and slower rate of rise of spontaneous excitatory postsynaptic currents. Collectively, these changes are consistent with a model in which disease-associated tau species disrupt network connectivity and signaling. Our results suggest that the persistence of truncated tau in the brain may underpin the catastrophic synaptic dysfunction observed during the development and progression of human tauopathy.

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Neuronal Density Determines Network Connectivity and Spontaneous Activity in Cultured Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00914.2009 ◽

2010 ◽

Vol 104 (2) ◽

pp. 1052-1060 ◽

Cited By ~ 53

Author(s):

Miriam Ivenshitz ◽

Menahem Segal

Keyword(s):

Hippocampal Neurons ◽

Burst Size ◽

Dendritic Tree ◽

Network Connectivity ◽

Network Activity ◽

Burst Frequency ◽

Population Activity ◽

Neuronal Density ◽

Evolving Networks ◽

Dendritic Shaft

The effects of neuronal density on morphological and functional attributes of the evolving networks were studied in cultured dissociated hippocampal neurons. Plating at different densities affected connectivity among the neurons, such that sparse networks exhibited stronger synaptic connections between pairs of recorded neurons. This was associated with different patterns of spontaneous network activity with enhanced burst size but reduced burst frequency in the sparse cultures. Neuronal density also affected the morphology of the dendrites and spines of these neurons, such that sparse neurons had a simpler dendritic tree and fewer dendritic spines. Additionally, analysis of neurons transfected with PSD95 revealed that in sparse cultures the synapses are formed on the dendritic shaft, whereas in dense cultures the synapses are formed primarily on spine heads. These experiments provide important clues on the role of neuronal density in population activity and should yield new insights into the rules governing neuronal network connectivity.

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Integration of sleep homeostasis and navigation in Drosophila

10.1101/2020.07.23.217638 ◽

2020 ◽

Author(s):

Andres Flores Valle ◽

Pedro J. Gonçalves ◽

Johannes D. Seelig

Keyword(s):

Structural Changes ◽

Brain Area ◽

Network Connectivity ◽

Central Complex ◽

Head Direction ◽

Sleep Phase ◽

Plasticity Mechanism ◽

Sleep Homeostasis ◽

The Face ◽

The Brain

ABSTRACTDuring sleep, the brain undergoes dynamic and structural changes. In Drosophila, such changes have been observed in the central complex, a brain area important for sleep control and navigation. The connectivity of the central complex raises the question about how navigation, and specifically the head direction system, can operate in the face of sleep related plasticity.To address this question, we develop a model that integrates sleep homeostasis and head direction. We show that by introducing plasticity, the head direction system can function in a stable way by balancing plasticity in connected circuits that encode sleep pressure. With increasing sleep pressure, the head direction system nevertheless becomes unstable and a sleep phase with a different plasticity mechanism is introduced to reset network connectivity.The proposed integration of sleep homeostasis and head direction circuits captures features of their neural dynamics observed in flies and mice.

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Integration of sleep homeostasis and navigation in Drosophila

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009088 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009088

Author(s):

Andres Flores-Valle ◽

Pedro J. Gonçalves ◽

Johannes D. Seelig

Keyword(s):

Structural Changes ◽

Brain Area ◽

Network Connectivity ◽

Central Complex ◽

Head Direction ◽

Sleep Phase ◽

Plasticity Mechanism ◽

Sleep Homeostasis ◽

The Face ◽

The Brain

During sleep, the brain undergoes dynamic and structural changes. In Drosophila, such changes have been observed in the central complex, a brain area important for sleep control and navigation. The connectivity of the central complex raises the question about how navigation, and specifically the head direction system, can operate in the face of sleep related plasticity. To address this question, we develop a model that integrates sleep homeostasis and head direction. We show that by introducing plasticity, the head direction system can function in a stable way by balancing plasticity in connected circuits that encode sleep pressure. With increasing sleep pressure, the head direction system nevertheless becomes unstable and a sleep phase with a different plasticity mechanism is introduced to reset network connectivity. The proposed integration of sleep homeostasis and head direction circuits captures features of their neural dynamics observed in flies and mice.

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Native Ubiquitin Structural Changes Resulting from Complexation with β-methylamino-L-alanine (BMAA)

10.26434/chemrxiv.12996335.v1 ◽

2020 ◽

Author(s):

Katie Mae Wilson ◽

Aurora Burkus-Matesevac ◽

Samuel Maddox ◽

Christopher Chouinard

Keyword(s):

Structural Changes ◽

Noncovalent Complex ◽

Unfolded Protein ◽

Protein Size ◽

High Concentrations ◽

The Unfolded Protein Response ◽

Critical Binding ◽

Protein Response ◽

The Brain ◽

Lateral Sclerosis

β-methylamino-L-alanine (BMAA) has been linked to the development of neurodegenerative (ND) symptoms following chronic environmental exposure through water and dietary sources. The brains of those affected by this condition, often referred to as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), have exhibited the presence of plaques and neurofibrillary tangles (NFTs) from protein aggregation. Although numerous studies have sought to better understand the correlation between BMAA exposure and onset of ND symptoms, no definitive link has been identified. One prevailing hypothesis is that BMAA acts a small molecule ligand, complexing with critical proteins in the brain and reducing their function. The objective of this research was to investigate the effects of BMAA exposure on the native structure of ubiquitin. We hypothesized that formation of a Ubiquitin+BMAA noncovalent complex would alter the protein’s structure and folding and ultimately affect the ubiquitinproteasome system (UPS) and the unfolded protein response (UPR). Ion mobility-mass spectrometry revealed that at sufficiently high concentrations BMAA did in fact form a noncovalent complex with ubiquitin, however similar complexes were identified for a range of additional amino acids. Collision induced unfolding (CIU) was used to interrogate the unfolding dynamics of native ubiquitin and these Ubq-amino acid complexes and it was determined that complexation with BMAA led to a significant alteration in native protein size and conformation, and this complex required considerably more energy to unfold. This indicates that the complex remains more stable under native conditions and this may indicate that BMAA has attached to a critical binding location.

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Native Ubiquitin Structural Changes Resulting from Complexation with β-methylamino-L-alanine (BMAA)

10.26434/chemrxiv.12996335 ◽

2020 ◽

Author(s):

Katie Mae Wilson ◽

Aurora Burkus-Matesevac ◽

Samuel Maddox ◽

Christopher Chouinard

Keyword(s):

Structural Changes ◽

Noncovalent Complex ◽

Unfolded Protein ◽

Protein Size ◽

High Concentrations ◽

The Unfolded Protein Response ◽

Critical Binding ◽

Protein Response ◽

The Brain ◽

Lateral Sclerosis

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Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity

Developmental Cognitive Neuroscience ◽

10.1016/j.dcn.2021.101000 ◽

2021 ◽

pp. 101000

Author(s):

Moriah E. Thomason ◽

Ava C. Palopoli ◽

Nicki N. Jariwala ◽

Denise M. Werchan ◽

Alan Chen ◽

...

Keyword(s):

Network Connectivity ◽

Brain Network ◽

Brain Network Connectivity ◽

The Brain

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Energy constraints on brain network formation

Scientific Reports ◽

10.1038/s41598-021-91250-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kosuke Takagi

Keyword(s):

Network Formation ◽

Cost Minimization ◽

Brain Network ◽

Network Activity ◽

Rich Functionality ◽

Energy Constraints ◽

Dependent Form ◽

Statistical Similarity ◽

Simple Ratio ◽

The Brain

AbstractEnergy constraints are a fundamental limitation of the brain, which is physically embedded in a restricted space. The collective dynamics of neurons through connections enable the brain to achieve rich functionality, but building connections and maintaining activity come at a high cost. The effects of reducing these costs can be found in the characteristic structures of the brain network. Nevertheless, the mechanism by which energy constraints affect the organization and formation of the neuronal network in the brain is unclear. Here, it is shown that a simple model based on cost minimization can reproduce structures characteristic of the brain network. With reference to the behavior of neurons in real brains, the cost function was introduced in an activity-dependent form correlating the activity cost and the wiring cost as a simple ratio. Cost reduction of this ratio resulted in strengthening connections, especially at highly activated nodes, and induced the formation of large clusters. Regarding these network features, statistical similarity was confirmed by comparison to connectome datasets from various real brains. The findings indicate that these networks share an efficient structure maintained with low costs, both for activity and for wiring. These results imply the crucial role of energy constraints in regulating the network activity and structure of the brain.

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The brain timewise: how timing shapes and supports brain function

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0170 ◽

2015 ◽

Vol 370 (1668) ◽

pp. 20140170 ◽

Cited By ~ 39

Author(s):

Riitta Hari ◽

Lauri Parkkonen

Keyword(s):

Human Brain ◽

Brain Imaging ◽

Brain Function ◽

Temporal Dynamics ◽

Generative Models ◽

Network Activity ◽

Brain Diseases ◽

Specific Information ◽

Non Invasive ◽

The Brain

We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the dynamics of the human brain with non-invasive measurements. Accurate timing is important for the interplay of neurons, neuronal circuitries, brain areas and human individuals. In the human brain, multiple temporal integration windows are hierarchically organized, with temporal scales ranging from microseconds to tens and hundreds of milliseconds for perceptual, motor and cognitive functions, and up to minutes, hours and even months for hormonal and mood changes. Accurate timing is impaired in several brain diseases. From the current repertoire of non-invasive brain imaging methods, only magnetoencephalography (MEG) and scalp electroencephalography (EEG) provide millisecond time-resolution; our focus in this paper is on MEG. Since the introduction of high-density whole-scalp MEG/EEG coverage in the 1990s, the instrumentation has not changed drastically; yet, novel data analyses are advancing the field rapidly by shifting the focus from the mere pinpointing of activity hotspots to seeking stimulus- or task-specific information and to characterizing functional networks. During the next decades, we can expect increased spatial resolution and accuracy of the time-resolved brain imaging and better understanding of brain function, especially its temporal constraints, with the development of novel instrumentation and finer-grained, physiologically inspired generative models of local and network activity. Merging both spatial and temporal information with increasing accuracy and carrying out recordings in naturalistic conditions, including social interaction, will bring much new information about human brain function.

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The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer's disease

Journal of Internal Medicine ◽

10.1111/joim.12164 ◽

2013 ◽

Vol 275 (4) ◽

pp. 418-427 ◽

Cited By ~ 31

Author(s):

X. Li ◽

T.-Q. Li ◽

N. Andreasen ◽

M. K. Wiberg ◽

E. Westman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Structural Changes ◽

The Brain

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Blockage of IL-17 Ameliorates Aβ-Induced Neurotoxicity and Cognitive Decline

10.21203/rs.3.rs-742937/v1 ◽

2021 ◽

Author(s):

Yulan Liu ◽

Yang Meng ◽

Chenliang Zhou ◽

Wenfang Xia ◽

Lu Wang ◽

...

Keyword(s):

Cognitive Decline ◽

Lateral Ventricle ◽

Hippocampal Neurons ◽

Cognitive Impairments ◽

Critical Role ◽

Synaptic Dysfunction ◽

Neural Damage ◽

Primary Hippocampal Neurons ◽

The Impact ◽

Aβ Production

Abstract BackgroundNeuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease (AD), particularly in amyloid-β (Aβ) production. But the impact of the cytokine, interleukin-17A (IL-17) on the course of AD has not been well defined. The goal was to determine the effect of IL-17 on neural damage and whether IL-17 inhibitor (Y-320) could ameliorate Aβ-induced neurotoxicity and cognitive decline.MethodsThe expression level of IL-17 was analyzed in APP/PS1 mice. Then IL-17 was injected into the lateral ventricle of C57BL WT mice and roles on synaptic dysfunction and cognitive impairments were examined. Aβ42 was injected into the lateral ventricle of to mimic Aβ42 model mice. The effects of IL-17 inhibitor by oral gavage on Aβ42-induced neurotoxicity and cognitive decline were examined. ResultsWe found that IL-17 was increased in the hippocampus of APP/PS1 transgenic mouse, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Furthermore, we reported that IL-17 was administrated in primary hippocampal neurons, leading to neural damage and synaptic dysfunction. At the same time, IL-17 caused synaptic dysfunction and cognitive impairments accompanying with increased of Aβ levels in mice. In addition, we found that Y-320 could rescue Aβ42–induced neural damage in primary hippocampal neurons, and ameliorate neuronal damage and cognitive impairments in Aβ42 model mice. Interestingly, we observed that IL-17 upregulated the production of soluble amyloid precursor protein β (sAPPβ) and phosphorylation of APP at T668 (pT668), moreover, Y-320 inhibited the Aβ production by down-regulation the sAPPβ and pT668. Conclusions Blockage of IL-17 might ameliorate Aβ-induced neurotoxicity and cognitive decline. These results strongly demonstrate a potential therapeutic role for IL-17 inhibitor in AD.

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