Shaping Dendritic NMDA Spikes by Timed Synaptic Inhibition: Implications for Branch-Specific Synaptic Plasticity and I/O Properties of Cortical Neurons

2018 ◽  
Author(s):  
Michael Doron ◽  
Giuseppe Chindemi ◽  
Eilif Muller ◽  
Henry Markram ◽  
Idan Segev
Keyword(s):  
Synaptic Plasticity ◽  
Cortical Neurons ◽  
Synaptic Inhibition

scholarly journals Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Emma M. Perkins ◽  
Karen Burr ◽  
Poulomi Banerjee ◽  
Arpan R. Mehta ◽  
Owen Dando ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Cortical Neurons ◽  
Electrode Array ◽  
Repeat Expansion ◽  
Cortical Network ◽  
Synaptic Function ◽  
Network Activity ◽  
Cortical Function ◽  
Network Function

Abstract Background Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear. Methods To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling. Results We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD. Conclusion These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.

scholarly journals All-Trans Retinoic Acid induces synaptic plasticity in human cortical neurons

2020 ◽  
Author(s):  
Maximilian Lenz ◽  
Pia Kruse ◽  
Amelie Eichler ◽  
Julia Muellerleile ◽  
Jakob Straehle ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Cortical Neurons ◽  
Mrna Translation ◽  
Dependent Manner ◽  
Human Cortex ◽  
Functional Changes ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Structural And Functional Properties

ABSTRACTA defining feature of the brain is its ability to adapt structural and functional properties of synaptic contacts in an experience-dependent manner. In the human cortex direct experimental evidence for synaptic plasticity is currently missing. Here, we probed plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid, which has been suggested as medication for the treatment of neuropsychiatric disorders, e.g., Alzheimer’s disease. Our experiments demonstrate coordinated structural and functional changes of excitatory synapses of superficial (layer 2/3) pyramidal neurons in the presence of all-trans retinoic acid. This synaptic adaptation is accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and requires mRNA-translation. We conclude that all-trans retinoic acid is a potent mediator of synaptic plasticity in the adult human cortex.

scholarly journals Timed Synaptic Inhibition Shapes NMDA Spikes, Influencing Local Dendritic Processing and Global I/O Properties of Cortical Neurons

Cell Reports ◽  
2017 ◽  
Vol 21 (6) ◽  
pp. 1550-1561 ◽  
Author(s):  
Michael Doron ◽  
Giuseppe Chindemi ◽  
Eilif Muller ◽  
Henry Markram ◽  
Idan Segev
Keyword(s):  
Cortical Neurons ◽  
Synaptic Inhibition ◽  
Dendritic Processing

scholarly journals Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

2015 ◽  
Vol 35 (9) ◽  
pp. 1557-1572 ◽  
Author(s):  
Shinya Kusakari ◽  
Fumihito Saitow ◽  
Yukio Ago ◽  
Koji Shibasaki ◽  
Miho Sato-Hashimoto ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cortical Neurons ◽  
Tyrosine Phosphatase ◽  
Hippocampal Slices ◽  
Memory Formation ◽  
Conditional Knockout ◽  
Abnormal Behavior ◽  
Erk Activation ◽  
Cultured Cortical Neurons ◽  
Forebrain Neurons

Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

scholarly journals Comparative chromatin accessibility upon BDNF-induced neuronal activity delineates neuronal regulatory elements

2021 ◽  
Author(s):  
Ignacio L. Ibarra ◽  
Vikram S. Ratnu ◽  
Lucia Gordillo ◽  
In-Young Hwang ◽  
Luca Mariani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Cortical Neurons ◽  
Complex Traits ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Control ◽  
Comparative Genomic ◽  
Regulatory Sequences

Neuronal activity induced by brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences decreased BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal activity.

scholarly journals Burst Synchronization in A Scale-Free Neuronal Network with Inhibitory Spike-Timing-Dependent Plasticity

2018 ◽  
Author(s):  
Sang-Yoon Kim ◽  
Woochang Lim
Keyword(s):  
Synaptic Plasticity ◽  
Network Architecture ◽  
Neuronal Population ◽  
Matthew Effect ◽  
Spike Timing ◽  
Synaptic Inhibition ◽  
Spike Timing Dependent Plasticity ◽  
Dependent Plasticity ◽  
Scale Free ◽  
Burst Synchronization

We are concerned about burst synchronization (BS), related to neural information processes in health and disease, in the Barabasi-Albert scale-free network (SFN) composed of inhibitory bursting Hindmarsh-Rose neurons. This inhibitory neuronal population has adaptive dynamic synaptic strengths governed by the inhibitory spike-timing-dependent plasticity (iSTDP). In previous works without considering iSTDP, BS was found to appear in a range of noise intensities for fixed synaptic inhibition strengths. In contrast, in our present work, we take into consideration iSTDP and investigate its effect on BS by varying the noise intensity. Our new main result is to find occurrence of a Matthew effect in inhibitory synaptic plasticity: good BS gets better via LTD, while bad BS get worse via LTP. This kind of Matthew effect in inhibitory synaptic plasticity is in contrast to that in excitatory synaptic plasticity where good (bad) synchronization gets better (worse) via LTP (LTD). We note that, due to inhibition, the roles of LTD and LTP in inhibitory synaptic plasticity are reversed in comparison with those in excitatory synaptic plasticity. Moreover, emergences of LTD and LTP of synaptic inhibition strengths are intensively investigated via a microscopic method based on the distributions of time delays between the preand the post-synaptic burst onset times. Finally, in the presence of iSTDP we investigate the effects of network architecture on BS by varying the symmetric attachment degree l* and the asymmetry parameter Δl in the SFN.

Regulation of Chloride Gradients and Neural Plasticity

2019 ◽  
Author(s):  
Jimena Perez-Sanchez ◽  
Yves De Koninck
Keyword(s):  
Synaptic Plasticity ◽  
Neural Plasticity ◽  
Neuronal Excitability ◽  
Dynamic Effect ◽  
Synaptic Inhibition ◽  
Gamma Aminobutyric Acid ◽  
Chloride Homeostasis ◽  
System P ◽  
Dual Action ◽  
The Central Nervous System

One of the most remarkable properties of neural circuits is the ability to restructure their synaptic connections throughout life. This synaptic plasticity allows neurons to structurally reorganize and adapt their function in response to experience. Among the multiple mechanisms that can modulate this property is synaptic inhibition by gamma-Aminobutyric acid (GABA) and/or glycine ionotropic receptors, which allow the flow of chloride and bicarbonate ions through the membrane. Neurons rely upon tight regulation of intracellular chloride for efficient inhibition through these receptors. The maintenance of chloride gradients is important not only to determine the strength of synaptic inhibition but also to determine its nature. Indeed, this inhibition can be hyperpolarizing or depolarizing, or with no outright change in the membrane potential. Despite the fact that membrane depolarization is commonly associated with excitation, depolarizing GABA/glycine can also produce inhibition, thereby highlighting the dual action of these neurotransmitters. Several considerations must be taken into account in order to allow depolarizing GABA/glycine responses to be excitatory. On the other hand, chloride homeostasis is never steady-state and even small changes of chloride across the membrane can impact the strength of inhibition. This dynamic effect has a direct impact on neuronal excitability and makes its regulation by changes in chloride gradients a highly tunable mechanism. Furthermore, increased excitability may also open a window for system refinement changes, such as synaptic plasticity. Indeed, the regulation of chloride homeostasis may underlie periods of enhanced plasticity, such as during early development. Finally, disruption of chloride gradients arises as a hub for pathology, which is evidenced in multiple disorders in the central nervous system.

scholarly journals Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

2015 ◽  
Vol 112 (43) ◽  
pp. E5883-E5890 ◽  
Author(s):  
Natasha K. Hussain ◽  
Gareth M. Thomas ◽  
Junjie Luo ◽  
Richard L. Huganir
Keyword(s):  
Signal Transduction ◽  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Signal Transduction Pathway ◽  
Cognitive Disorders ◽  
Surface Expression ◽  
Nucleotide Exchange

AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR–Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine–nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition.

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