Dendrite-Specific Amplification of Weak Synaptic Input during Network Activity In Vivo

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00860-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Maria Mensch ◽

Jade Dunot ◽

Sandy M. Yishan ◽

Samuel S. Harris ◽

Aline Blistein ◽

...

Keyword(s):

Neuronal Activity ◽

Ex Vivo ◽

Long Term Potentiation ◽

Network Activity ◽

Strongly Correlated ◽

App Processing ◽

Term Potentiation ◽

Hippocampal Network

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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Small footprint optoelectrodes using ring resonators for passive light localization

Microsystems & Nanoengineering ◽

10.1038/s41378-021-00263-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vittorino Lanzio ◽

Gregory Telian ◽

Alexander Koshelev ◽

Paolo Micheletti ◽

Gianni Presti ◽

...

Keyword(s):

State Of The Art ◽

Three Dimensional ◽

Network Activity ◽

Ring Resonators ◽

Spatiotemporal Resolution ◽

Optical Ring Resonators ◽

Light Localization ◽

Order Of Magnitude ◽

Small Footprint

AbstractThe combination of electrophysiology and optogenetics enables the exploration of how the brain operates down to a single neuron and its network activity. Neural probes are in vivo invasive devices that integrate sensors and stimulation sites to record and manipulate neuronal activity with high spatiotemporal resolution. State-of-the-art probes are limited by tradeoffs involving their lateral dimension, number of sensors, and ability to access independent stimulation sites. Here, we realize a highly scalable probe that features three-dimensional integration of small-footprint arrays of sensors and nanophotonic circuits to scale the density of sensors per cross-section by one order of magnitude with respect to state-of-the-art devices. For the first time, we overcome the spatial limit of the nanophotonic circuit by coupling only one waveguide to numerous optical ring resonators as passive nanophotonic switches. With this strategy, we achieve accurate on-demand light localization while avoiding spatially demanding bundles of waveguides and demonstrate the feasibility with a proof-of-concept device and its scalability towards high-resolution and low-damage neural optoelectrodes.

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Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.01126.2007 ◽

2008 ◽

Vol 99 (3) ◽

pp. 1394-1407 ◽

Cited By ~ 28

Author(s):

Sarah Potez ◽

Matthew E. Larkum

Keyword(s):

High Frequency ◽

Pyramidal Neurons ◽

Animal Experiments ◽

Apical Dendrite ◽

Network Activity ◽

Calcium Spikes ◽

Firing Properties ◽

The Impact

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

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Changes of synaptic input frequency in the dentate gyrus induce feedback regulation of synaptic strength in vivo

Neuroscience Research ◽

10.1016/j.neures.2010.07.1505 ◽

2010 ◽

Vol 68 ◽

pp. e340

Author(s):

Daisuke Miyamoto ◽

Hiroshi Nomura ◽

Norio Matsuki

Keyword(s):

Dentate Gyrus ◽

Synaptic Input ◽

Feedback Regulation ◽

Synaptic Strength ◽

Input Frequency

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Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function

10.1101/2021.11.01.466782 ◽

2021 ◽

Author(s):

Alexei M. Bygrave ◽

Ayesha Sengupta ◽

Ella P. Jackert ◽

Mehroz Ahmed ◽

Beloved Adenuga ◽

...

Keyword(s):

Inhibitory Interneuron ◽

Nmda Receptor Antagonist ◽

Specific Protein ◽

Network Activity ◽

Scaffolding Protein ◽

Inhibitory Interneurons ◽

Cell Type ◽

Cell Type Specific

Synapses in the brain exhibit cell–type–specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell–type–specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron–specific synapse–enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd–95. Intriguingly, we show that Btbd11 can undergo liquid–liquid phase separation when expressed with Psd–95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin–positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell–type–specific protein that supports glutamatergic synapse function in inhibitory interneurons–with implication for circuit function and animal behavior.

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Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

10.1101/2021.05.12.443879 ◽

2021 ◽

Author(s):

Alison G Costigan ◽

Katja Umla-Runge ◽

C John Evans ◽

Rachel Raybould ◽

Kim S Graham ◽

...

Keyword(s):

Resting State ◽

Genetic Risk ◽

Occipital Cortex ◽

Network Activity ◽

Resonance Spectroscopy ◽

1H Mrs ◽

Gaba A ◽

Spatio Temporal ◽

E4 Allele

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ~20-30 have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN) which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, nor in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Results suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or indeed may precede, alterations in local resting-state PMC neurotransmitters, thus informing the spatio-temporal order and the cause/effect dynamic of neuroimaging differences in APOE E4 carriers.

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Homeostatic plasticity rules control the wiring of axo-axonic synapses at the axon initial segment

10.1101/453753 ◽

2018 ◽

Cited By ~ 1

Author(s):

Alejandro Pan-Vazquez ◽

Winnie Wefelmeyer ◽

Victoria Gonzalez Sabater ◽

Juan Burrone

Keyword(s):

Initial Segment ◽

Pyramidal Cells ◽

Axon Initial Segment ◽

Homeostatic Plasticity ◽

Network Activity ◽

Gabaergic Interneuron ◽

Chandelier Cells ◽

Local Circuits ◽

And Function

AbstractGABAergic interneurons are chiefly responsible for controlling the activity of local circuits in the cortex1,2. However, the rules that govern the wiring of interneurons are not well understood3. Chandelier cells (ChCs) are a type of GABAergic interneuron that control the output of hundreds of neighbouring pyramidal cells through axo-axonic synapses which target the axon initial segment (AIS)4. Despite their importance in modulating circuit activity, our knowledge of the development and function of axo-axonic synapses remains elusive. In this study, we investigated the role of activity in the formation and plasticity of ChC synapses. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window resulted in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the AIS showed that axo-axonic synapses were depolarising during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted in an increase in axo-axonic synapses. We propose that the direction of ChC plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.

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Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve membrane synchrony

10.1101/454702 ◽

2018 ◽

Author(s):

Richard Dewell ◽

Fabrizio Gabbiani

Keyword(s):

Synaptic Input ◽

Collision Detection ◽

Dendritic Morphology ◽

Synaptic Integration ◽

Neuronal Membrane ◽

Hcn Channels ◽

Movement Detector ◽

Membrane Impedance ◽

Wide Range

Brains processes information through the coordinated efforts of billions of individual neurons, each encoding a small part of the overall information stream. Central to this is how neurons integrate and transform complex patterns of synaptic inputs. The neuronal membrane impedance sets the gain and timing for synaptic integration, determining a neuron's ability to discriminate between synaptic input patterns. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper, Schistocerca americana. We examined how the cellular properties of the lobula giant movement detector (LGMD) neuron are tuned to enable the discrimination of synaptic input patterns key to its role in collision detection. We found that two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide gated (HCN) channels and by muscarine sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD's natural range of membrane potentials and synaptic input frequencies. Additionally, we found that the LGMD's branching morphology increased the gain and decreased delays associated with the mapping of synaptic input currents to membrane potential. We investigated whether other branching dendritic morphologies fulfill a similar function and found this to be true for a wide range of morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings further our understanding of the integration properties of individual neurons by showing the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration.

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Oxytocin shapes spontaneous activity patterns in the developing visual cortex by activating somatostatin interneurons

10.1101/866251 ◽

2019 ◽

Cited By ~ 1

Author(s):

Paloma P Maldonado ◽

Alvaro Nuno-Perez ◽

Jan Kirchner ◽

Elizabeth Hammock ◽

Julijana Gjorgjieva ◽

...

Keyword(s):

Visual Cortex ◽

Spontaneous Activity ◽

Sensory Processing ◽

Activity Patterns ◽

Network Activity ◽

Synaptic Connections ◽

Pairwise Correlations ◽

Early Brain Development

SummarySpontaneous network activity shapes emerging neuronal circuits during early brain development, however how neuromodulation influences this activity is not fully understood. Here, we report that the neuromodulator oxytocin powerfully shapes spontaneous activity patterns. In vivo, oxytocin strongly decreased the frequency and pairwise correlations of spontaneous activity events in visual cortex (V1), but not in somatosensory cortex (S1). This differential effect was a consequence of oxytocin only increasing inhibition in V1 and increasing both inhibition and excitation in S1. The increase in inhibition was mediated by the depolarization and increase in excitability of somatostatin+ (SST) interneurons specifically. Accordingly, silencing SST+ neurons pharmacogenetically fully blocked oxytocin’s effect on inhibition in vitro as well its effect on spontaneous activity patterns in vivo. Thus, oxytocin decreases the excitatory/inhibitory ratio and modulates specific features of V1 spontaneous activity patterns that are crucial for refining developing synaptic connections and sensory processing later in life.

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