scholarly journals Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

2022 ◽  
Vol 15 ◽  
Author(s):  
Enrico Cherubini ◽  
Graziella Di Cristo ◽  
Massimo Avoli
Keyword(s):  
Autism Spectrum ◽  
Postnatal Period ◽  
Adult Brain ◽  
Postnatal Life ◽  
Neuronal Circuits ◽  
Brain Areas ◽  
Inhibitory Neurotransmitter ◽  
Morphological Alterations ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

The construction of the brain relies on a series of well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt to the external environment. Disruption of these processes leads to neurological and psychiatric disorders, which in many cases are manifest already early in postnatal life. GABA, the main inhibitory neurotransmitter in the adult brain is one of the major players in the early assembly and formation of neuronal circuits. In the prenatal and immediate postnatal period GABA, acting on GABAA receptors, depolarizes and excites targeted cells via an outwardly directed flux of chloride. In this way it activates NMDA receptors and voltage-dependent calcium channels contributing, through intracellular calcium rise, to shape neuronal activity and to establish, through the formation of new synapses and elimination of others, adult neuronal circuits. The direction of GABAA-mediated neurotransmission (depolarizing or hyperpolarizing) depends on the intracellular levels of chloride [Cl−]i, which in turn are maintained by the activity of the cation-chloride importer and exporter KCC2 and NKCC1, respectively. Thus, the premature hyperpolarizing action of GABA or its persistent depolarizing effect beyond the postnatal period, leads to behavioral deficits associated with morphological alterations and an excitatory (E)/inhibitory (I) imbalance in selective brain areas. The aim of this review is to summarize recent data concerning the functional role of GABAergic transmission in building up and refining neuronal circuits early in development and its dysfunction in neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia and epilepsy. In particular, we focus on novel information concerning the mechanisms by which alterations in cation-chloride co-transporters (CCC) generate behavioral and cognitive impairment in these diseases. We discuss also the possibility to re-establish a proper GABAA-mediated neurotransmission and excitatory (E)/inhibitory (I) balance within selective brain areas acting on CCC.

scholarly journals Generalized Anxiety Disorder in Adults: Focus on Pregabalin

2011 ◽  
Vol 3 ◽  
pp. CMPsy.S5069 ◽  
Author(s):  
Mark J. Boschen
Keyword(s):  
Anxiety Disorder ◽  
Generalized Anxiety Disorder ◽  
Preliminary Evidence ◽  
Future Research ◽  
Generalized Anxiety ◽  
Inhibitory Neurotransmitter ◽  
Ion Flow ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Flow Through

Generalized anxiety disorder (GAD) is a chronic illness which impacts significantly on an individual's functioning and quality of life. Pregabalin is a novel structural analogue of the inhibitory neurotransmitter GABA, acting to reduce calcium ion flow through the α2δ subunit of pre-synaptic voltage-dependent calcium channels. Pregabalin has been used in treatment of GAD in a total of eight published controlled trials. In each trial, pregabalin has demonstrated a superiority over placebo, with response rates of over 40% in all studies, including patients on lower doses. One study has provided preliminary evidence for the efficacy of pregabalin in treatment of GAD in older adults. Pregabalin is generally well tolerated, with the most common adverse events being dizziness and somnolence. Adverse effects are generally mild-to-moderate, and transient. Pregabalin has low abuse potential. Limitations of the current literature are discussed, and directions for future research are proposed.

scholarly journals Alterations of GABAergic Signaling in Autism Spectrum Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Rocco Pizzarelli ◽  
Enrico Cherubini
Keyword(s):  
Autism Spectrum Disorders ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Calcium Influx ◽  
Adult Life ◽  
Stereotyped Behavior ◽  
Autism Spectrum ◽  
Neuronal Circuits ◽  
Inhibitory Neurotransmitter ◽  
Spectrum Disorders

Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

scholarly journals Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity

2020 ◽  
pp. 107385842092137 ◽  
Author(s):  
Liam Carroll ◽  
Sven Braeutigam ◽  
John M. Dawes ◽  
Zeljka Krsnik ◽  
Ivica Kostovic ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Postnatal Period ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Brain Areas ◽  
Multiple Routes ◽  
Spectrum Disorders ◽  
Phenotypic Specificity

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.

scholarly journals Boosting L-type Ca2+ channel activity in tuberous sclerosis mitigates excess glutamate receptors and seizures

2020 ◽  
Author(s):  
Farr Niere ◽  
Luisa P. Cacheaux ◽  
David C. Klorig ◽  
William C. Taylor ◽  
Thuy Smith ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tuberous Sclerosis ◽  
Drug Repositioning ◽  
Treatment Options ◽  
Significant Risk ◽  
Surface Expression ◽  
Autism Spectrum ◽  
Multisystem Disorder ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

AbstractTuberous sclerosis complex (TS) is a dominant, multisystem disorder with devastating neurological symptoms. Approximately 85% of TS patients suffer from epilepsy over their lifespan and roughly 25-50% of those patients develop Autism Spectrum Disorder (1, 2). Current seizure therapies are effective in some, but not all, and often have significant risk factors associated with their use (1, 3). Thus, there is a critical need for new medication development or drug repositioning. Herein, we leveraged proteomic signatures of epilepsy and ASD, often comorbid in TS, to utilize an in silco approach to identify new drug therapies for TS-related seizures. We have discovered that activation of L-type voltage dependent calcium channels (L-VDCC) by Bay-K8644 (BayK) in a preclinical mouse model of TS curtails seizure frequency. Remarkably, at the molecular level, excess expression of ionotropic, AMPA-subtype glutamate (GluA) receptors is rescued by the administration of BayK. As added proof of BayK working through L-VDCC to regulate GluA levels, we found that increasing expression of alpha2delta2 (α2δ2), an auxiliary calcium channel subunit that boosts L-VDCC surface expression, similarly lowers the surface expression of dendritic GluA in TS. These BayK-induced molecular and functional alterations may underlie the longer lifespan of TS mice treated with BayK.Significance StatementCausal mechanisms of Tuberous Sclerosis (TS)-associated neurological disorders are under-characterized and treatment options are lacking. Using a computational approach of mTOR/DJ-1 target mRNAs to predict new medications, we report that boosting L-type voltage-dependent Ca2+ channel (L-VDCC) activity in a preclinical TS mouse model that exhibits a deficit in dendritic L-VDCC activity ameliorates key molecular and electrophysiological pathologies that are predicted to underlie seizures. Additionally, boosting L-VDCC activity extends lifespan. Restoring the mTOR/DJ-1 pathway upstream of L-VDCC, therefore, may serve as a new therapeutic avenue to mitigate seizures and mortality in TS.

scholarly journals The TLR-2/TonEBP signaling pathway regulates 29-kDa fibronectin fragment-dependent expression of matrix metalloproteinases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyun Sook Hwang ◽  
Mi Hyun Lee ◽  
Hyun Ah Kim
Keyword(s):  
Matrix Metalloproteinases ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Nuclear Accumulation ◽  
Activated T Cells ◽  
Inflammatory Conditions ◽  
Enhancer Binding Protein ◽  
Fibronectin Fragments ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

AbstractTonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality. However, recent studies have shown that it also modulates immune responses under inflammatory conditions independently of hyperosmolality. Fibronectin fragments (FN-fs), which are abundant in the synovial fluid of patients with osteoarthritis (OA), induce expression of matrix metalloproteinases (MMPs) via the toll-like receptor-2 (TLR-2) signaling pathway. In this study we examined whether TonEBP is involved in 29-kDa FN-f-induced expression of MMPs. The expression of TonEBP was significantly higher in human osteoarthritis compared with normal cartilage samples. 29-kDa FN-f affected the expression of MMPs 1, 3, and 13 via TonEBP, and expression and nuclear accumulation of TonEBP were induced by activation of the phospholipase C/NF-κB/MAPK signaling pathway and, in particular, modulated by TLR-2. In addition, 29-kDa FN-f induced the expression of osmoregulatory genes, including Tau-T, SMIT, and AR, as well as voltage-dependent calcium channels via the TonEBP/TLR-2 signaling pathway. These results show that 29-kDa FN-f upregulates MMPs in chondrocytes via the TLR-2/TonEBP signaling pathway.

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