The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission

Abstract Classically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.

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BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

Neural Plasticity ◽

10.1155/2014/128631 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Emily Petrus ◽

Hey-Kyoung Lee

Keyword(s):

Synaptic Plasticity ◽

Visual Cortex ◽

Synaptic Transmission ◽

Sensory Experience ◽

Synaptic Function ◽

Excitatory Synaptic Transmission ◽

Early Gene ◽

Dependent Manner ◽

Homeostatic Synaptic Plasticity ◽

Activity Dependent

Alzheimer’s disease (AD) is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ) peptides. Studies over the past few decades suggest that Aβis produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions forβ- andγ-secretases, the two key enzymes that produce Aβby sequentially processing the amyloid precursor protein (APP), have been discovered over recent years. In particular, activity-dependent production of Aβhas been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβproduction and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronalβ-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

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Spinophilin limits GluN2B-containing NMDAR activity and sequelae associated with excessive hippocampal NMDAR function

10.1101/2020.12.30.424812 ◽

2021 ◽

Author(s):

Asma B. Salek ◽

Ruchi Bansal ◽

Nicolas F. Berbari ◽

Anthony J. Baucum

Keyword(s):

Cognitive Flexibility ◽

Hippocampal Neurons ◽

Calcium Influx ◽

Surface Expression ◽

List Type ◽

Dependent Manner ◽

Caspase Cleavage ◽

Calcium Dependent ◽

Apoptotic Pathways

ABSTRACTN-methyl-D-Aspartate receptors (NMDARs) are calcium-permeable ion channels that are ubiquitously expressed within the glutamatergic postsynaptic density. Phosphorylation of NMDAR subunits defines receptor activity and surface localization. Modulation of NMDAR phosphorylation by kinases and phosphatases regulates calcium entering the cell and subsequent activation of calcium-dependent processes. Spinophilin is the major synaptic protein phosphatase 1 (PP1) targeting protein that controls phosphorylation of myriad substrates via targeting or inhibition of PP1. Spinophilin limits NMDAR function in a PP1-dependent manner and we have previously shown that spinophilin sequesters PP1 away from the GluN2B subunit of the NMDAR, which results in increased phosphorylation of Ser-1284. However, how spinophilin modifies NMDAR function is unclear. Herein, we detail that while Ser-1284 phosphorylation increases calcium influx via GluN2B-containing NMDARs, overexpression of spinophilin decreases GluN2B-containing NMDAR activity by decreasing its surface expression. In hippocampal neurons isolated from spinophilin knockout animals there is an increase in cleaved caspase-3 levels compared to wildtype mice; however, this effect is not exclusively due to NMDAR activation; suggesting multiple putative mechanisms by which spinophilin may modulate caspase cleavage. Behaviorally, our data suggest that spinophilin knockout mice have deficits in spatial cognitive flexibility, a behavior associated GluN2B function within the hippocampus. Taken together, our data demonstrate a unique mechanism by which spinophilin modulates GluN2B containing NMDAR phosphorylation, channel function, and trafficking and that loss of spinophilin promotes pathological sequelae associated with GluN2B dysfunction.HIGHLIGHTSSpinophilin bidirectionally regulates GluN2B-containing NMDAR function.Loss of spinophilin in primary hippocampal neurons increases a pro-apoptotic marker.Loss of spinophilin in vivo decreases measures of spatial cognitive flexibility.Graphical AbstractSpinophilin increases the phosphorylation of Ser-1284 on GluN2B, thereby enhancing calcium influx through the GluN2B containing NMDARs. In contrast, spinophilin limits GluN2B-containing surface expression putatively due to modulation of GluN2B interactions with endocytotic proteins. Since the second effect of spinophilin occurs independent of the first, we observe an overall decrease in calcium influx through GluN2B containing NMDARs when spinophilin is present. This low, basal calcium influx is less likely to be promote calcium-dependent activation of caspase and downstream apoptotic pathways and permits flexible search strategies and behaviors. In the absence of spinophilin, the spinophilin-driven internalization of the receptors is decreased, more receptors are expressed on the surface and calcium influx into the cell is increased. This high levels of intracellular calcium triggers apoptotic pathways leading to cell death. This impact may be more dramatic in cells with high expression of GluN2B-containing NMDA receptors. This loss of spinophilin reduces cognitive flexibility in hippocampal dependent tasks.

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Presynaptic Release Probability Is Increased in Hippocampal Neurons From ASIC1 Knockout Mice

Journal of Neurophysiology ◽

10.1152/jn.00940.2007 ◽

2008 ◽

Vol 99 (2) ◽

pp. 426-441 ◽

Cited By ~ 36

Author(s):

Jun-Hyeong Cho ◽

Candice C. Askwith

Keyword(s):

Synaptic Transmission ◽

Knockout Mice ◽

Hippocampal Neurons ◽

Wild Type ◽

Single Action ◽

Release Probability ◽

Readily Releasable Pool ◽

Presynaptic Mechanisms ◽

Significant Difference ◽

Behavioral Impairments

Acid-sensing ion channels (ASICs) are H+-gated channels that produce transient cation currents in response to extracellular acid. ASICs are expressed in neurons throughout the brain, and ASIC1 knockout mice show behavioral impairments in learning and memory. The role of ASICs in synaptic transmission, however, is not thoroughly understood. We analyzed the involvement of ASICs in synaptic transmission using microisland cultures of hippocampal neurons from wild-type and ASIC knockout mice. There was no significant difference in single action potential (AP)–evoked excitatory postsynaptic currents (EPSCs) between wild-type and ASIC knockout neurons. However, paired-pulse ratios (PPRs) were reduced and spontaneous miniature EPSCs (mEPSCs) occurred at a higher frequency in ASIC1 knockout neurons compared with wild-type neurons. The progressive block of NMDA receptors by an open channel blocker, MK-801, was also faster in ASIC1 knockout neurons. The amplitude and decay time constant of mEPSCs, as well as the size and refilling of the readily releasable pool, were similar in ASIC1 knockout and wild-type neurons. Finally, the release probability, which was estimated directly as the ratio of AP-evoked to hypertonic sucrose-induced charge transfer, was increased in ASIC1 knockout neurons. Transfection of ASIC1a into ASIC1 knockout neurons increased the PPRs, suggesting that alterations in release probability were not the result of developmental compensation within the ASIC1 knockout mice. Together, these findings demonstrate that neurons from ASIC1 knockout mice have an increased probability of neurotransmitter release and indicate that ASIC1a can affect presynaptic mechanisms of synaptic transmission.

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Facilitation of Cortico–Amygdala Synapses by Nicotine: Activity-Dependent Modulation of Glutamatergic Transmission

Journal of Neurophysiology ◽

10.1152/jn.00933.2007 ◽

2008 ◽

Vol 99 (4) ◽

pp. 1988-1999 ◽

Cited By ~ 37

Author(s):

Li Jiang ◽

Lorna W. Role

Keyword(s):

Synaptic Transmission ◽

Prenatal Exposure ◽

Long Term Potentiation ◽

Cholinergic Innervation ◽

Dependent Manner ◽

Glutamatergic Transmission ◽

Basolateral Nucleus ◽

Cortical Inputs ◽

Activity Dependent ◽

Stimulation Of

The basolateral nucleus of the amygdala (BLA) receives cholinergic innervation from the basal forebrain and nicotine, via activation of neuronal nicotinic acetylcholine receptors (nAChRs), can improve performance in amygdala-based learning tasks. We tested the hypothesis that acute and prenatal nicotine exposure modulates cortico–amygdala synaptic transmission. We found that low-dose, single-trial exposures to nicotine can elicit lasting facilitation, the extent of which is dependent on the level of stimulation of the cortical inputs to the BLA. In addition, sustained facilitation is ablated by prenatal exposure to nicotine. This study examined synaptic transmission in 238 patch-clamp recordings from BLA neurons in acute slice from mouse brain. Pharmacological studies in wild-type and nAChR subunit knock-out mice reveal that activation of presynaptic α7, containing (α7*) and non-α7* nAChRs, facilitates glutamatergic transmission in an activity-dependent manner. Without prior stimulation, application of nicotine elicits modest and transient facilitation of glutamatergic postsynaptic currents (PSCs) in about 40% of BLA neurons. With low-frequency stimulation of cortical inputs nicotine elicits robust facilitation of transmission at about 60% of cortico–BLA synapses and synaptic strength remains elevated at about 40% of these connections for >15 min after nicotine washout. Following paired-pulse stimulation nicotine elicits long-lasting facilitation of glutamatergic transmission at about 70% of cortico–BLA connections. Nicotine reduces the threshold for activation of long-term potentiation of cortico–BLA synapses evoked by patterned stimulation. Prenatal exposure to nicotine reduced subsequent modulatory responses to acute nicotine application.

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Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Journal of Neurophysiology ◽

10.1152/jn.00667.2014 ◽

2015 ◽

Vol 113 (5) ◽

pp. 1493-1500 ◽

Cited By ~ 23

Author(s):

Hoyong Park ◽

Sungmin Kim ◽

Jeehae Rhee ◽

Hyeon-Joong Kim ◽

Jung-Soo Han ◽

...

Keyword(s):

Synaptic Transmission ◽

Lysophosphatidic Acid ◽

Hippocampal Neurons ◽

Neuronal Excitability ◽

Receptor Activation ◽

Cell System ◽

Adult Brain ◽

Synaptic Activity ◽

Dependent Manner ◽

Central Synapses

Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca2+ in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases.

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Activity-regulated synaptic targeting of lncRNA ADEPTR mediates structural plasticity by localizing Sptn1 and AnkB in dendrites

Science Advances ◽

10.1126/sciadv.abf0605 ◽

2021 ◽

Vol 7 (16) ◽

pp. eabf0605

Author(s):

Eddie Grinman ◽

Yoshihisa Nakahata ◽

Yosef Avchalumov ◽

Isabel Espadas ◽

Supriya Swarnkar ◽

...

Keyword(s):

Hippocampal Neurons ◽

Noncoding Rna ◽

Molecular Motor ◽

Structural Plasticity ◽

Dependent Manner ◽

Protein Coding ◽

Synaptic Targeting ◽

Conserved Sequence ◽

Activity Dependent

Activity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long noncoding transcriptome remains elusive. Here, we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—that is up-regulated and synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independently of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators ankyrin (AnkB) and spectrin (Sptn1) via a conserved sequence and is required for their dendritic localization. Together, this study demonstrates how activity-dependent synaptic targeting of an lncRNA mediates structural plasticity at the synapse.

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Astrocyte Networks and Epilepsy: When Stars Collide

Epilepsy Currents ◽

10.1111/j.1535-7511.2009.01310.x ◽

2009 ◽

Vol 9 (4) ◽

pp. 113-115 ◽

Cited By ~ 1

Author(s):

Michael Wong

Keyword(s):

Synaptic Transmission ◽

Gap Junctions ◽

Connexin 43 ◽

Molecular Mechanisms ◽

Epileptiform Activity ◽

Synaptic Activity ◽

Structural Basis ◽

Dependent Manner ◽

Domain Organization ◽

Activity Dependent

Loss of Astrocytic Domain Organization in the Epileptic Brain. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, Nedergaard M. J Neurosci 2008;28(13):3264–3276. Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission. Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Science 2008;322(5907):1551–1555. Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

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Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission

eLife ◽

10.7554/elife.51440 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Matthew P McCabe ◽

Erin R Cullen ◽

Caitlynn M Barrows ◽

Amy N Shore ◽

Katherine I Tooke ◽

...

Keyword(s):

Synaptic Transmission ◽

Hippocampal Neurons ◽

Mtor Signaling ◽

Postsynaptic Inhibition ◽

Major Mechanism ◽

Presynaptic Function ◽

Glutamatergic Synaptic Transmission ◽

Presynaptic Release ◽

Neuron Growth ◽

Cell Growth And Proliferation

Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR’s role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.

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Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner

The Journal of Cell Biology ◽

10.1083/jcb.201308026 ◽

2014 ◽

Vol 204 (5) ◽

pp. 759-775 ◽

Cited By ~ 29

Author(s):

Tony Cijsouw ◽

Jens P. Weber ◽

Jurjen H. Broeke ◽

Jantine A.C. Broek ◽

Desiree Schut ◽

...

Keyword(s):

Exchange Rates ◽

Hippocampal Neurons ◽

Fluorescence Recovery After Photobleaching ◽

Calcium Influx ◽

Dynamic Control ◽

Lateral Diffusion ◽

Nerve Terminals ◽

Dependent Manner ◽

Kinase C ◽

Vesicle Pool

Munc18-1 is a soluble protein essential for synaptic transmission. To investigate the dynamics of endogenous Munc18-1 in neurons, we created a mouse model expressing fluorescently tagged Munc18-1 from the endogenous munc18-1 locus. We show using fluorescence recovery after photobleaching in hippocampal neurons that the majority of Munc18-1 trafficked through axons and targeted to synapses via lateral diffusion together with syntaxin-1. Munc18-1 was strongly expressed at presynaptic terminals, with individual synapses showing a large variation in expression. Axon–synapse exchange rates of Munc18-1 were high: during stimulation, Munc18-1 rapidly dispersed from synapses and reclustered within minutes. Munc18-1 reclustering was independent of syntaxin-1, but required calcium influx and protein kinase C (PKC) activity. Importantly, a PKC-insensitive Munc18-1 mutant did not recluster. We show that synaptic Munc18-1 levels correlate with synaptic strength, and that synapses that recruit more Munc18-1 after stimulation have a larger releasable vesicle pool. Hence, PKC-dependent dynamic control of Munc18-1 levels enables individual synapses to tune their output during periods of activity.

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