scholarly journals Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology

2021 ◽  
Vol 22 (22) ◽  
pp. 12456
Author(s):  
Yuya Sakimoto ◽  
Paw Min-Thein Oo ◽  
Makoto Goshima ◽  
Itsuki Kanehisa ◽  
Yutaro Tsukada ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Gabaa Receptor ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Contextual Learning ◽  
Learning Performance ◽  
Inhibitory Synapses ◽  
Gamma Aminobutyric Acid ◽  
Contextual Memory ◽  
Spatiotemporal Information

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABAA receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.

scholarly journals Autism-Like Behavior in the Offspring of CYP11A1-Overexpressing Pregnant Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Tianying Pan ◽  
Chuan Jiang ◽  
Juan Cheng ◽  
Jiang Xie ◽  
Xinghui Liu ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Receptor Expression ◽  
Gamma Aminobutyric Acid ◽  
Primary Microglia ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Necrosis Factor Alpha ◽  
Sd Rats

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental disorders that are characterized by impaired social behavior and communication as well as repetitive behavior and restricted interests. Prenatal exposure to high levels of testosterone and preeclampsia are thought to be risk factors of ASD. We had previously reported that overexpression of the mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1) could lead to both preeclampsia-like symptoms and increased testosterone levels in pregnant rats. In this study, we investigated the association between high CYP11A1 levels in pregnant rats and autism-like behavior in their offspring. Timed-pregnant Sprague-Dawley (SD) rats were injected with CYP11A1 gene-carrying adenoviruses on gestational day 8.5, and their offspring were then compared with those from timed-pregnant control SD rats. Compared with their control counterparts, the offspring of the CYP11A1-ovexpressing dams displayed more symptoms of anxiety and spent less time in social interactions and more time in self-grooming and rearing, all indicators of autism-like behavior. Sequencing of the transcriptome in primary microglia from the offspring of CYP11A1-overexpressing dams revealed that immune pathways were highly activated, and the gamma-aminobutyric acid type A (GABAA) receptor genes were among the top differentially expressed genes. Using primary microglia cultures generated from neonatal rats, tumor necrosis factor-alpha expression was found to be elevated in the cells transfected with CYP11A1-carrying adenoviruses. Additionally, the offspring of CYP11A1-overexpressing dams displayed dysregulated GABAA receptor expression. Taken together, these results suggest that abnormal CYP11A1 gene expression in pregnant rats could lead to microglial immune activation and dysregulated GABAA receptor expression in their offspring and thereby anxiety and autism-related behavior. Our study suggests that the pathways regulated by CYP11A1 could be promising preventative and therapeutic targets for ASD.

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.

Disruption of the Prefrontal Cortex Improves Implicit Contextual Memory-Guided Attention: Combined Behavioral and Electrophysiological Evidence

2019 ◽  
Vol 30 (1) ◽  
pp. 20-30 ◽  
Author(s):  
Mario Rosero Pahi ◽  
Juliana Cavalli ◽  
Frauke Nees ◽  
Herta Flor ◽  
Jamila Andoh
Keyword(s):  
Prefrontal Cortex ◽  
Brain Activity ◽  
Learning Task ◽  
Contextual Learning ◽  
Learning Performance ◽  
Oscillatory Activity ◽  
Beta Band ◽  
Top Down ◽  
Contextual Memory ◽  
Electrical Brain Activity

Abstract Many studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays an important role in top-down cognitive control over intentional and deliberate behavior. However, recent studies have reported that DLPFC-mediated top-down control interferes with implicit forms of learning. Here we used continuous theta-burst stimulation (cTBS) combined with electroencephalography to investigate the causal role of DLPFC in implicit contextual memory-guided attention. We aimed to test whether transient disruption of the DLPFC would interfere with implicit learning performance and related electrical brain activity. We applied neuronavigation-guided cTBS to the DLPFC or to the vertex as a control region prior to the performance of an implicit contextual learning task. We found that cTBS applied over the DLPFC significantly improved performance during implicit contextual learning. We also noted that beta-band (13–19 Hz) oscillatory power was reduced at fronto-central channels about 140 to 370 ms after visual stimulus onset in cTBS DLPFC compared with cTBS vertex. Taken together, our results provide evidence that DLPFC-mediated top-down control interferes with contextual memory-guided attention and beta-band oscillatory activity.

The quantitative structure-activity relationships between GABAA receptor and ligands based on binding interface characteristic

2020 ◽  
Vol 16 ◽  
Author(s):  
Shu Cheng ◽  
Yanrui Ding
Keyword(s):  
Gabaa Receptor ◽  
Molecular Descriptors ◽  
Qsar Model ◽  
Coefficient Of Determination ◽  
Gradient Boosting ◽  
Receptor Interaction ◽  
Gamma Aminobutyric Acid ◽  
Quantitative Structure ◽  
Binding Interface ◽  
Structure Activity

Background: Quantitative Structure Activity Relationship (QSAR) methods based on machine learning play a vital role in predicting biological effect. Objective: Considering the characteristics of the binding interface between ligands and the inhibitory neurotransmitter Gamma Aminobutyric Acid A(GABAA) receptor, we built a QSAR model of ligands that bind to the human GABAA receptor. Method: After feature selection with Mean Decrease Impurity, we selected 53 from 1,286 docked ligand molecular descriptors. Three QSAR models are built using gradient boosting regression tree algorithm based on the different combinations of docked ligand molecular descriptors and ligand-receptor interaction characteristics. Results: The features of the optimal QSAR model contain both the docked ligand molecular descriptors and ligand-receptor interaction characteristics. The Leave-One-Out-Cross-Validation (Q2 LOO) of the optimal QSAR model is 0.8974, the Coefficient of Determination (R2) for the testing set is 0.9261, the Mean Square Error (MSE) is 0.1862. We also used this model to predict the pIC50 of two new ligands, the differences between the predicted and experimental pIC50 are -0.02 and 0.03 respectively. Conclusion : We found the BELm2, BELe2, MATS1m, X5v, Mor08v, and Mor29m are crucial features, which can help to build the QSAR model more accurately.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

scholarly journals Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

2021 ◽  
Vol 22 (15) ◽  
pp. 7887
Author(s):  
Carmen Nanclares ◽  
Andres Mateo Baraibar ◽  
Alfonso Araque ◽  
Paulo Kofuji
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Neuronal Excitability ◽  
Active Role ◽  
Ionic Homeostasis ◽  
Neuronal Communication ◽  
Structural Support

Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

scholarly journals Sensory over-responsivity is related to GABAergic inhibition in thalamocortical circuits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily T. Wood ◽  
Kaitlin K. Cummings ◽  
Jiwon Jung ◽  
Genevieve Patterson ◽  
Nana Okada ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Sensory Information ◽  
Network Connectivity ◽  
Sensory Stimulation ◽  
Autism Spectrum ◽  
Future Research ◽  
Resonance Spectroscopy ◽  
Gamma Aminobutyric Acid ◽  
Sensory Stimuli ◽  
Brain Responses

AbstractSensory over-responsivity (SOR), extreme sensitivity to or avoidance of sensory stimuli (e.g., scratchy fabrics, loud sounds), is a highly prevalent and impairing feature of neurodevelopmental disorders such as autism spectrum disorders (ASD), anxiety, and ADHD. Previous studies have found overactive brain responses and reduced modulation of thalamocortical connectivity in response to mildly aversive sensory stimulation in ASD. These findings suggest altered thalamic sensory gating which could be associated with an excitatory/inhibitory neurochemical imbalance, but such thalamic neurochemistry has never been examined in relation to SOR. Here we utilized magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects. Although there were no diagnostic group differences in neurochemical concentrations in either region, within the ASD group, SOR severity correlated negatively with thalamic GABA (r = −0.48, p < 0.05) and positively with somatosensory glutamate (r = 0.68, p < 0.01). Further, in the ASD group, thalamic GABA concentration predicted altered connectivity with regions previously implicated in SOR. These variations in GABA and associated network connectivity in the ASD group highlight the potential role of GABA as a mechanism underlying individual differences in SOR, a major source of phenotypic heterogeneity in ASD. In ASD, abnormalities of the thalamic neurochemical balance could interfere with the thalamic role in integrating, relaying, and inhibiting attention to sensory information. These results have implications for future research and GABA-modulating pharmacologic interventions.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

2021 ◽  
Author(s):  
Ahmed Eltokhi ◽  
Miguel A. Gonzalez-Lozano ◽  
Lars-Lennart Oettl ◽  
Andrey Rozov ◽  
Claudia Pitzer ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Social Interaction ◽  
Social Behavior ◽  
Ampa Receptors ◽  
Signal To Noise Ratio ◽  
Signal Transmission ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Strong Impact ◽  
Odor Processing

AbstractMutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

scholarly journals Exploiting heterogeneity in operational neural networks by synaptic plasticity

2021 ◽  
Author(s):  
Serkan Kiranyaz ◽  
Junaid Malik ◽  
Habib Ben Abdallah ◽  
Turker Ince ◽  
Alexandros Iosifidis ◽  
...  
Keyword(s):  
Neural Networks ◽  
Synaptic Plasticity ◽  
Network Model ◽  
Neuron Model ◽  
Linear Operators ◽  
Training Data ◽  
Learning Performance ◽  
Minimal Network ◽  
Hidden Layer ◽  
Hidden Neurons

AbstractThe recently proposed network model, Operational Neural Networks (ONNs), can generalize the conventional Convolutional Neural Networks (CNNs) that are homogenous only with a linear neuron model. As a heterogenous network model, ONNs are based on a generalized neuron model that can encapsulate any set of non-linear operators to boost diversity and to learn highly complex and multi-modal functions or spaces with minimal network complexity and training data. However, the default search method to find optimal operators in ONNs, the so-called Greedy Iterative Search (GIS) method, usually takes several training sessions to find a single operator set per layer. This is not only computationally demanding, also the network heterogeneity is limited since the same set of operators will then be used for all neurons in each layer. To address this deficiency and exploit a superior level of heterogeneity, in this study the focus is drawn on searching the best-possible operator set(s) for the hidden neurons of the network based on the “Synaptic Plasticity” paradigm that poses the essential learning theory in biological neurons. During training, each operator set in the library can be evaluated by their synaptic plasticity level, ranked from the worst to the best, and an “elite” ONN can then be configured using the top-ranked operator sets found at each hidden layer. Experimental results over highly challenging problems demonstrate that the elite ONNs even with few neurons and layers can achieve a superior learning performance than GIS-based ONNs and as a result, the performance gap over the CNNs further widens.

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