Chemico-genetic discovery of molecules underlying tripartite-synaptic function 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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Enhanced LTP of population spikes in the dentate gyrus of mice haploinsufficient for neurobeachin

Scientific Reports ◽

10.1038/s41598-020-72925-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Julia Muellerleile ◽

Aline Blistein ◽

Astrid Rohlmann ◽

Frederieke Scheiwe ◽

Markus Missler ◽

...

Keyword(s):

Dentate Gyrus ◽

Granule Cell ◽

Field Potential ◽

Synaptic Function ◽

Spatial Learning And Memory ◽

Neurotransmitter Receptor ◽

Cell Excitability ◽

Neuronal Protein ◽

Electrophysiological Recordings

Abstract Deletion of the autism candidate molecule neurobeachin (Nbea), a large PH-BEACH-domain containing neuronal protein, has been shown to affect synaptic function by interfering with neurotransmitter receptor targeting and dendritic spine formation. Previous analysis of mice lacking one allele of the Nbea gene identified impaired spatial learning and memory in addition to altered autism-related behaviours. However, no functional data from living heterozygous Nbea mice (Nbea+/−) are available to corroborate the behavioural phenotype. Here, we explored the consequences of Nbea haploinsufficiency on excitation/inhibition balance and synaptic plasticity in the intact hippocampal dentate gyrus of Nbea+/− animals in vivo by electrophysiological recordings. Based on field potential recordings, we show that Nbea+/− mice display enhanced LTP of the granule cell population spike, but no differences in basal synaptic transmission, synapse numbers, short-term plasticity, or network inhibition. These data indicate that Nbea haploinsufficiency causes remarkably specific alterations to granule cell excitability in vivo, which may contribute to the behavioural abnormalities in Nbea+/− mice and to related symptoms in patients.

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The impact of bilingualism on brain reserve and metabolic connectivity in Alzheimer's dementia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610909114 ◽

2017 ◽

Vol 114 (7) ◽

pp. 1690-1695 ◽

Cited By ~ 88

Author(s):

Daniela Perani ◽

Mohsen Farsad ◽

Tommaso Ballarini ◽

Francesca Lubian ◽

Maura Malpetti ◽

...

Keyword(s):

Neuroprotective Effect ◽

Alzheimer’S Dementia ◽

Synaptic Function ◽

Compensatory Mechanisms ◽

Neuroprotective Effects ◽

Alzheimer's Dementia ◽

Bilingual Speakers ◽

Metabolic Connectivity ◽

The Impact

Cognitive reserve (CR) prevents cognitive decline and delays neurodegeneration. Recent epidemiological evidence suggests that lifelong bilingualism may act as CR delaying the onset of dementia by ∼4.5 y. Much controversy surrounds the issue of bilingualism and its putative neuroprotective effects. We studied brain metabolism, a direct index of synaptic function and density, and neural connectivity to shed light on the effects of bilingualism in vivo in Alzheimer’s dementia (AD). Eighty-five patients with probable AD and matched for disease duration (45 German-Italian bilingual speakers and 40 monolingual speakers) were included. Notably, bilingual individuals were on average 5 y older than their monolingual peers. In agreement with our predictions and with models of CR, cerebral hypometabolism was more severe in the group of bilingual individuals with AD. The metabolic connectivity analyses crucially supported the neuroprotective effect of bilingualism by showing an increased connectivity in the executive control and the default mode networks in the bilingual, compared with the monolingual, AD patients. Furthermore, the degree of lifelong bilingualism (i.e., high, moderate, or low use) was significantly correlated to functional modulations in crucial neural networks, suggesting both neural reserve and compensatory mechanisms. These findings indicate that lifelong bilingualism acts as a powerful CR proxy in dementia and exerts neuroprotective effects against neurodegeneration. Delaying the onset of dementia is a top priority of modern societies, and the present in vivo neurobiological evidence should stimulate social programs and interventions to support bilingual or multilingual education and the maintenance of the second language among senior citizens.

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Upregulated SK2 Expression and Impaired CaMKII Phosphorylation Are Shared Synaptic Defects Between 16p11.2del and 129S:Δdisc1 Mutant Mice

ASN NEURO ◽

10.1177/1759091418817641 ◽

2018 ◽

Vol 10 ◽

pp. 175909141881764 ◽

Cited By ~ 1

Author(s):

Razia Sultana ◽

Tanya Ghandi ◽

Alexandra M. Davila ◽

Charles C. Lee ◽

Olalekan M. Ogundele

Keyword(s):

Prefrontal Cortex ◽

Cognitive Disorders ◽

Synaptic Function ◽

Mutant Mice ◽

Neural Recordings ◽

Calcium Calmodulin Dependent ◽

Aspartate Receptor ◽

Cornu Ammonis ◽

Small Conductance

Ion channel gating and kinase regulation of N-methyl-D-aspartate receptor 1 activity are fundamental mechanisms that govern synaptic plasticity. In this study, we showed that two mutant models (16p11.2del and Δdisc1) that recapitulate aspects of human cognitive disorders shared a similar defect in N-methyl-D-aspartate receptor 1-dependent synaptic function. Our results demonstrate that the expression of small-conductance potassium channels (SK2 or KCa2.2) was significantly upregulated in the hippocampus and prefrontal cortex of 16p11.2del and 129S: Δdisc1 mutant mice. Likewise, both mutant strains exhibited an impairment of T286 phosphorylation of calcium-calmodulin-dependent kinase II (CaMKII) in the hippocampus and prefrontal cortex. In vivo neural recordings revealed that increased SK2 expression and impaired T286 phosphorylation of CaMKII coincide with a prolonged interspike interval in the hippocampal cornu ammonis-1 (CA1) field for both 16p11.2del and 129S: Δdisc1 mutant mice. These findings suggest that alteration of small conductance channels and T286 phosphorylation of CaMKII are likely shared factors underlying behavioral changes in these two genetic mouse models.

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