scholarly journals Dopamine modulates the integrity of the perisynaptic extracellular matrix at excitatory synapses

2019 ◽  
Author(s):  
Jessica Mitlöhner ◽  
Rahul Kaushik ◽  
Hartmut Niekisch ◽  
Armand Blondiaux ◽  
Christine E. Gee ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cortical Neurons ◽  
Receptor Activation ◽  
Synaptic Activity ◽  
Excitatory Synapses ◽  
Intracellular Calcium Signaling ◽  
Rat Cortical Neurons ◽  
Synaptic Receptors

SummaryIn the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

scholarly journals Dopamine Receptor Activation Modulates the Integrity of the Perisynaptic Extracellular Matrix at Excitatory Synapses

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 260 ◽  
Author(s):  
Jessica Mitlöhner ◽  
Rahul Kaushik ◽  
Hartmut Niekisch ◽  
Armand Blondiaux ◽  
Christine E. Gee ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cortical Neurons ◽  
Receptor Activation ◽  
Synaptic Activity ◽  
Excitatory Synapses ◽  
Intracellular Calcium Signaling ◽  
Rat Cortical Neurons ◽  
Synaptic Receptors

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), which control the functions and mobility of synaptic receptors as well as the diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We showed that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM both in vivo and in vitro. ADAMTS immunoreactivity was detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We have outlined a molecular scenario of how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

scholarly journals Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

2020 ◽  
Vol 27 (10) ◽  
pp. 2810-2827 ◽  
Author(s):  
Björn Friedhelm Vahsen ◽  
Vinicius Toledo Ribas ◽  
Jonas Sundermeyer ◽  
Alexander Boecker ◽  
Vivian Dambeck ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Axonal Degeneration ◽  
Dominant Negative ◽  
Focal Lesion ◽  
Pathological Feature ◽  
Nerve Crush ◽  
Cord Injury ◽  
Rat Cortical Neurons

Abstract Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

scholarly journals Nafamostat and sepimostat identified as novel neuroprotective agents via NR2B N-methyl-D-aspartate receptor antagonism using a rat retinal excitotoxicity model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masahiro Fuwa ◽  
Masaaki Kageyama ◽  
Koji Ohashi ◽  
Masaaki Sasaoka ◽  
Ryuichi Sato ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Nr2b Subunit ◽  
Neuroprotective Effects ◽  
Receptor Antagonism ◽  
Rat Brain Membranes ◽  
Rat Cortical Neurons ◽  
Orally Active ◽  
Related Compounds

AbstractIn addition to its role in the treatment of pancreatitis, the serine protease inhibitor nafamostat exhibits a retinal protective effect. However, the exact mechanisms underlying this effect are unknown. In this study, the neuroprotective effects of nafamostat and its orally active derivative sepimostat against excitotoxicity were further characterised in vitro and in vivo. In primary rat cortical neurons, nafamostat completely suppressed N-methyl-D-aspartate (NMDA)-induced cell death. Intravitreal injection of nafamostat and sepimostat protected the rat retina against NMDA-induced degeneration, whereas the structurally related compounds, gabexate and camostat, did not. The neuroprotective effects of nafamostat and the NR2B antagonist ifenprodil were remarkably suppressed by spermidine, a naturally occurring polyamine that modulates the NR2B subunit. Both nafamostat and sepimostat inhibited [3H]ifenprodil binding to fractionated rat brain membranes. Thus, nafamostat and sepimostat may exert neuroprotective effects against excitotoxic retinal degeneration through NMDA receptor antagonism at the ifenprodil-binding site of the NR2B subunit.

Mechanical perturbation of cultured cortical neurons reveals a stretch-induced delayed depolarization

1995 ◽  
Vol 74 (6) ◽  
pp. 2767-2773 ◽  
Author(s):  
S. J. Tavalin ◽  
E. F. Ellis ◽  
L. S. Satin
Keyword(s):  
Brain Injury ◽  
Cortical Neurons ◽  
Receptor Activation ◽  
Neuronal Firing ◽  
Neonatal Rat ◽  
Resting Membrane Potential ◽  
Cell Stretch ◽  
Cultured Cortical Neurons ◽  
Rat Cortical Neurons

1. An in vitro cellular model of injury was used to elucidate mechanisms contributing to traumatic brain injury (TBI). Neonatal rat cortical neurons cultured on a flexible silastic membrane were stretched rapidly and reversibly by a 50-ms pulse of pressurized air. 2. Sublethal cell stretch depolarized neuronal resting membrane potential by approximately 10 mV but only if cells were incubated for 1 h after injury. Stretch-induced delayed depolarization (or SIDD) returned to baseline values within 24 h. 3. SIDD was dependent on the degree of cell stretch and required neuronal firing, calcium entry, and N-methyl-D-aspartate receptor activation for its induction but not its maintainance. 4. Similarities between SIDD and TBI suggest that SIDD may play a role in brain injury.

scholarly journals Impact of Network Activities on Neuronal Properties in Corticothalamic Systems

2001 ◽  
Vol 86 (1) ◽  
pp. 1-39 ◽  
Author(s):  
M. Steriade
Keyword(s):  
Membrane Potential ◽  
Cortical Neurons ◽  
Cortical Cell ◽  
Input Resistance ◽  
Synaptic Activity ◽  
Brain Functions ◽  
Intact Brain ◽  
Intact Cortex

Data from in vivo and in vitro experiments are discussed to emphasize that synaptic activities in neocortex and thalamus have a decisive impact on intrinsic neuronal properties in intact-brain preparations under anesthesia and even more so during natural states of vigilance. Thus the firing patterns of cortical neuronal types are not inflexible but may change with the level of membrane potential and during periods rich in synaptic activity. The incidences of some cortical cell classes (defined by their responses to depolarizing current pulses) are different in isolated cortical slabs in vivo or in slices maintained in vitro compared with the intact cortex of naturally awake animals. Network activities, which include the actions of generalized modulatory systems, have a profound influence on the membrane potential, apparent input resistance, and backpropagation of action potentials. The analysis of various oscillatory types leads to the conclusion that in the intact brain, there are no “pure” rhythms, generated in simple circuits, but complex wave sequences (consisting of different, low- and fast-frequency oscillations) that result from synaptic interactions in corticocortical and corticothalamic neuronal loops under the control of activating systems arising in the brain stem core or forebrain structures. As an illustration, it is shown that the neocortex governs the synchronization of network or intrinsically generated oscillations in the thalamus. The rhythmic recurrence of spike bursts and spike trains fired by thalamic and cortical neurons during states of decreased vigilance may lead to plasticity processes in neocortical neurons. If these phenomena, which may contribute to the consolidation of memory traces, are not constrained by inhibitory processes, they induce seizures in which the neocortex initiates the paroxysms and controls their thalamic reflection. The results indicate that intact-brain preparations are necessary to investigate global brain functions such as behavioral states of vigilance and paroxysmal activities.

scholarly journals High current optogenetic channels for stimulation and inhibition of primary rat cortical neurons

2017 ◽  
Author(s):  
Lei Jin ◽  
Eike Frank Joest ◽  
Wenfang Li ◽  
Shiqiang Gao ◽  
Andreas Offenhäusser ◽  
...  
Keyword(s):  
Neural Development ◽  
Cortical Neurons ◽  
Single Channel ◽  
Chloride Concentration ◽  
Neuronal Firing ◽  
High Current ◽  
Neuronal Inhibition ◽  
Rat Cortical Neurons

AbstractChR2-XXL and GtACR1 are currently the cation and anion ends of the optogenetic single channel current range. These were used in primary rat cortical neurons in vitro to manipulate neuronal firing patterns. ChR2-XXL provides high cation currents via elevated light sensitivity and a prolonged open state. Stimulating ChR2-XXL expressing putative presynaptic neurons induced neurotransmission. Moreover, stable depolarisation block could be generated in single neurons using ChR2-XXL, proving that ChR2-XXL is a promising candidate for in vivo applications of optogenetics, for example to treat peripheral neuropathic pain. We also addressed an anion channelrhodopsin (GtACR1) for the next generation of optogenetic neuronal inhibition in primary rat cortical neurons. GtACR1‘s light-gated chloride conduction was verified in primary neurons and the efficient photoinhibition of action potentials, including spontaneous activity, was shown. Our data also implies that the chloride concentration in neurons decreases during neural development. In both cases, we find surprising applications of these high current channels. For ChR2-XXL inhibition and stimulation are possible, while for GtACR1 the role of Cl−during neural development becomes a new optogenetic target.

Impact of Spontaneous Synaptic Activity on the Resting Properties of Cat Neocortical Pyramidal Neurons In Vivo

1998 ◽  
Vol 79 (3) ◽  
pp. 1450-1460 ◽  
Author(s):  
Denis Paré ◽  
Eric Shink ◽  
Hélène Gaudreau ◽  
Alain Destexhe ◽  
Eric J. Lang
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Synaptic Activity ◽  
Intact Brain ◽  
Lower Temperature ◽  
The Impact ◽  
Neocortical Pyramidal Neurons

Paré, Denis, Eric Shink, Hélène Gaudreau, Alain Destexhe, and Eric J. Lang. Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons in vivo. J. Neurophysiol. 79: 1450–1460, 1998. The frequency of spontaneous synaptic events in vitro is probably lower than in vivo because of the reduced synaptic connectivity present in cortical slices and the lower temperature used during in vitro experiments. Because this reduction in background synaptic activity could modify the integrative properties of cortical neurons, we compared the impact of spontaneous synaptic events on the resting properties of intracellularly recorded pyramidal neurons in vivo and in vitro by blocking synaptic transmission with tetrodotoxin (TTX). The amount of synaptic activity was much lower in brain slices (at 34°C), as the standard deviation of the intracellular signal was 10–17 times lower in vitro than in vivo. Input resistances ( R ins) measured in vivo during relatively quiescent epochs (“control R ins”) could be reduced by up to 70% during periods of intense spontaneous activity. Further, the control R ins were increased by ∼30–70% after TTX application in vivo, approaching in vitro values. In contrast, TTX produced negligible R in changes in vitro (∼4%). These results indicate that, compared with the in vitro situation, the background synaptic activity present in intact networks dramatically reduces the electrical compactness of cortical neurons and modifies their integrative properties. The impact of the spontaneous synaptic bombardment should be taken into account when extrapolating in vitro findings to the intact brain.

scholarly journals The Interplay between Synaptic Activity and Neuroligin Function in the CNS

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Xiaoge Hu ◽  
Jian-hong Luo ◽  
Junyu Xu
Keyword(s):  
Synapse Formation ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Spectrum Disorders ◽  
Cell Adhesion Proteins ◽  
The Relationship

Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.

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