Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo

At chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.

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Sensory Transmission is Bi-directionally Modulated by Astrocytic Ca2+ in Barrel Cortex of Behaving Mice

10.21203/rs.3.rs-199750/v1 ◽

2021 ◽

Author(s):

Simeng Gu ◽

Wei Wang ◽

Kuan Zhang ◽

Rou Feng ◽

Naling Li ◽

...

Keyword(s):

Sensory Input ◽

Barrel Cortex ◽

Synaptic Function ◽

Metabolic Clearance ◽

Sleep State ◽

Two Photon Microscopy ◽

Two Photon ◽

Sensory Transmission

Abstract Different effects of astrocyte during sleep and awake have been extensively studied, especially for metabolic clearance by the glymphatic system, which works during sleep and stops working during waking states. However, how astrocytes contribute to modulation of sensory transmission during sleep and awake animals remain largely unknown. Recent advances in genetically encoded Ca2+ indicators have provided a wealth of information on astrocytic Ca2+, especially in their fine perisynaptic processes, where astrocytic Ca2+ most likely affects the synaptic function. Here we use two-photon microscopy to image astrocytic Ca2+ signaling in freely moving mice trained to run on a wheel in combination with in vivo whole-cell recordings to evaluate the role of astrocytic Ca2+ signaling in different behavior states. We found that there are two kinds of astrocytic Ca2+ signaling: a small long-lasting Ca2+ increase during sleep state and a sharp widespread but short-long-lasting Ca2+ spike when the animal was awake (fluorescence increases were 23.2 ± 14.4% for whisker stimulation at sleep state, compared with 73.3 ± 11.7% for at awake state, paired t-test, p < 0.01). The small Ca2+ transients decreased extracellular K+, hyperpolarized the neurons, and suppressed sensory transmission; while the large Ca2+ wave enhanced sensory input, contributing to reliable sensory transmission in aroused states. Locus coeruleus activation works as a switch between these two kinds of astrocytic Ca2+ elevation. Thus, we show that cortical astrocytes play an important role in processing of sensory input. These two types of events appear to have different pharmacological sources and may play a different role in facilitating the efficacy of sensory transmission.

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Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽

10.7554/elife.33092 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 5

Author(s):

Anna R Moore ◽

Sarah E Richards ◽

Katelyn Kenny ◽

Leandro Royer ◽

Urann Chan ◽

...

Keyword(s):

Neuronal Excitability ◽

Ocular Dominance ◽

Sensory Experience ◽

Cellular Level ◽

Synaptic Function ◽

Intrinsic Excitability ◽

Spontaneous Firing ◽

Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

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Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit

Nature Communications ◽

10.1038/s41467-021-26575-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jung-Hwan Choi ◽

Lauren Bayer Horowitz ◽

Niels Ringstad

Keyword(s):

Synaptic Vesicles ◽

Glutamate Release ◽

Glutamate Transporter ◽

Synaptic Function ◽

Functional Coupling ◽

Glutamate Signaling ◽

C Elegans ◽

Vesicular Transporters ◽

Chemical Synapses

AbstractAt chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.

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CSPα reduces aggregates and rescues striatal dopamine release in αsynuclein transgenic mice

10.1101/2020.07.31.229153 ◽

2020 ◽

Author(s):

L Caló ◽

E Hidari ◽

M Wegrzynowicz ◽

JW Dalley ◽

BL Schneider ◽

...

Keyword(s):

Dopamine Release ◽

Early Stage ◽

Synaptic Function ◽

Snare Complex ◽

Early Event ◽

Vesicle Recycling ◽

Cysteine String Protein ◽

And Function

AbstractαSynuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and αsynuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like αsynuclein, chaperones the SNARE complex assembly and neurotransmitter release. αSynuclein can rescue neurodegeneration in CSPαKO mice. However, whether αsynuclein aggregation alters CSPα expression and function is unknown. Here we show that αsynuclein aggregation at the synapse induces a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with αsynuclein aggregates and in vivo reduces synaptic αsynuclein aggregates restoring normal dopamine release in 1-120hαsyn mice. These novel findings reveal a mechanism by which αsynuclein aggregation alters CSPα at the synapse, and show that CSPα rescues αsynuclein aggregation-related phenotype in 1-120hαsyn mice similar to the effect of αsynuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage PD.

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