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 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.

Tuberous Sclerosis Complex

2010 ◽  
Author(s):  
Paolo Curatolo ◽  
Elisa D’Agati
Keyword(s):  
Cell Proliferation ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Behavioral Problems ◽  
Clinical Manifestations ◽  
Autism Spectrum ◽  
Multisystem Disorder ◽  
Cell Proliferation And Differentiation ◽  
Genes Encoding ◽  
Minor Criteria

Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disorder that can cause circumscribed, benign, noninvasive lesions in any organ (Curatolo 2003; Gomez 1999). It affects about 1 newborn in every 6000 (Osborne, Fryer et al. 1991). The term tuberous sclerosis of the cerebral convolutions was used more than a century ago to describe the distinctive findings at autopsy in some patients with seizures and mental subnormality; the term tuberous describes the potato-like consistency of gyri with hypertrophic sclerosis (Bourneville 1880). The wide range of organs affected by the disease implies an important role for the TSC1 and TSC2 genes encoding hamartin and tuberin in the regulation of cell proliferation and differentiation. Tuberous sclerosis complex is a protean disease: the random distribution, number, size, and location of lesions cause varied clinical manifestations, involving the brain, skin, eyes, heart, kidney, lung (Curatolo et al. 2008). Some lesions, such as renal angiomyolipomas, do not occur until a certain age; by contrast, cardiac rhabdomyomas appear in the fetus and almost always regress spontaneously in infancy (Sosunov et al. 2008). About 85% of children and adolescents with TSC have central nervous system (CNS) manifestations, including epilepsy, learning difficulties, mental retardation, challenging behavioral problems, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), which can be associated with the structural CNS features generally seen in TSC (Curatolo et al. 1991; Gillberg et al. 1994). Abnormalities of neuronal migration and cellular differentiation, and excessive cell proliferation, all contribute to the formation of the various TSC brain lesions including cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), and widespread gray and white matter abnormalities, these latter being identified even in patients with average intelligence (Ridler et al. 2001; de Vries et al. 2005; Ridler et al. 2007). Further characterization of these typical lesions has been provided by progress in structural and functional imaging (DiMario 2004; Luat et al. 2007). Major and minor criteria exist to diagnose TSC (Table 32.1). The diagnosis is made when two major features, or one major and two minor ones, can be detected.

Hearing and Neurodevelopmental Outcomes of Young Infants with Parechovirus-A and Enterovirus Meningitis: Cohort Study in Singapore Children and Literature Review

2020 ◽  
Author(s):  
Elis Yuexian Lee ◽  
Jessica Hui Yin Tan ◽  
Chew Thye Choong ◽  
Nancy Wen Sim Tee ◽  
Chia Yin Chong ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Oropharyngeal Dysphagia ◽  
Significant Risk ◽  
Developmental Outcomes ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Cortical Blindness ◽  
Speech Delay ◽  
Neurodevelopmental Outcomes ◽  
Young Infants

Abstract Parechovirus-A (PeV-A) and Enterovirus (EV) commonly cause childhood aseptic meningitis. Bacterial meningitis in children has been associated with devastating long-term sequelae. However, developmental outcomes are unclear in Parechovirus meningitis. This study aims to review the clinical findings and developmental outcomes of infants with PeV-A and EV meningitis. We performed a retrospective study of infants aged 90 days or younger being admitted to our hospital with PeV-A meningitis between November 2015 and July 2017, with positive cerebrospinal fluid (CSF) PeV-A PCR and negative blood and CSF bacterial cultures. Hearing and neurodevelopmental outcomes were compared with a previous cohort of infants aged 90 days or younger with EV meningitis admitted from January 2015 to December 2015. A total of 161 infants were included in our study, of which 68 infants (42.2%) had PeV-A meningitis and 93 infants (57.8%) had EV meningitis. We assessed their developmental outcome at 6 months, 1 year, and 2 years post-meningitis. At 2 years post-meningitis, three infants with PeV-A meningitis had developmental delay (5.5%), whereas none with EV meningitis had developmental delay. One patient had speech delay and autism spectrum disorder, while two had mild speech delay. When compared with our cohort of EV meningitis ≤90 days old, children with PeV-A meningitis ≤90 days old were more likely to have developmental delay 2 years post-meningitis (odds ratio 2.4, 95% confidence interval 2.0–3.0, p = 0.043). None of the patients with PeV-A or EV meningitis had sensorineural hearing loss or neurological sequelae, such as cortical blindness, oropharyngeal dysphagia, hydrocephalus, epilepsy, or cerebral palsy. Infants with PeV-A meningitis had a significant risk of developmental delay 2 years post-meningitis compared with those with EV meningitis. It is important to follow-up the developmental milestones of infants diagnosed with PeV-A meningitis for at least 2 years; and when they develop developmental delay, to ensure that they receive appropriate intervention.

Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

2019 ◽  
Author(s):  
German I. Todorov ◽  
Karthikeyan Mayilvahanan ◽  
David Ashurov ◽  
Catarina Cunha
Keyword(s):  
Mouse Model ◽  
Autism Spectrum ◽  
Obsessive Compulsive ◽  
Cancer Treatments ◽  
Knock Out ◽  
Treatment Priority ◽  
Underlying Mechanisms ◽  
Knock Out Mice ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

Microbiota, Immune System and Autism Spectrum Disorders: An Integrative Model towards Novel Treatment Options

2020 ◽  
Vol 27 (31) ◽  
pp. 5119-5136 ◽  
Author(s):  
Barbara Carpita ◽  
Donatella Marazziti ◽  
Lionella Palego ◽  
Gino Giannaccini ◽  
Laura Betti ◽  
...  
Keyword(s):  
Immune System ◽  
Familial Aggregation ◽  
Treatment Options ◽  
Autism Spectrum ◽  
Integrative Model ◽  
Neural Basis ◽  
Integrative Framework ◽  
Intermediate Phenotypes ◽  
Close Relatives

Background: Autism Spectrum Disorder (ASD) is a condition strongly associated with genetic predisposition and familial aggregation. Among ASD patients, different levels of symptoms severity are detectable, while the presence of intermediate autism phenotypes in close relatives of ASD probands is also known in literature. Recently, increasing attention has been paid to environmental factors that might play a role in modulating the relationship between genomic risk and development and severity of ASD. Within this framework, an increasing body of evidence has stressed a possible role of both gut microbiota and inflammation in the pathophysiology of neurodevelopment. The aim of this paper is to review findings about the link between microbiota dysbiosis, inflammation and ASD. Methods: Articles ranging from 1990 to 2018 were identified on PUBMED and Google Scholar databases, with keyword combinations as: microbiota, immune system, inflammation, ASD, autism, broad autism phenotype, adult. Results: Recent evidence suggests that microbiota alterations, immune system and neurodevelopment may be deeply intertwined, shaping each other during early life. However, results from both animal models and human samples are still heterogeneous, while few studies focused on adult patients and ASD intermediate phenotypes. Conclusion: A better understanding of these pathways, within an integrative framework between central and peripheral systems, might not only shed more light on neural basis of ASD symptoms, clarifying brain pathophysiology, but it may also allow to develop new therapeutic strategies for these disorders, still poorly responsive to available treatments.

Co-Occurring Mood Problems in Autism Spectrum Disorder

2020 ◽  
pp. 27-51
Author(s):  
Virginia Carter Leno ◽  
Emily Simonoff
Keyword(s):  
Autism Spectrum Disorder ◽  
Service Use ◽  
Bipolar Depression ◽  
Behavioral Therapy ◽  
Treatment Options ◽  
Public Health Problem ◽  
Bipolar Disorders ◽  
Unipolar Depression ◽  
Autism Spectrum ◽  
Spectrum Disorder

Recent evidence suggests that individuals with autism spectrum disorder (ASD) experience depression at rates approximately four times greater than the general population. Co-occurring mood problems, including depressive and bipolar disorders, are associated with negative outcomes such as lower quality of life, increased adaptive behavior impairments, and greater service use. This chapter discusses what is known about the presentation of unipolar and bipolar depression in people with ASD and describes challenges to establishing sound prevalence estimates of mood disorders in ASD as they relate to methodological design issues and diagnostic assessment practices. It also provides an overview of potential vulnerability factors in the development of depression in this population; these areas of vulnerability include characteristics such as chronological age, cognitive ability, and ASD symptom severity, as well as those individual differences that may represent more direct mechanisms, for example, maladaptive coping styles, attentional biases, social reward profiles, and predisposition to rumination. The current research on interventions specifically designed to treat mood in people with ASD is very limited. However, promising treatments include adapted cognitive behavioral therapy and mindfulness-based approaches. Though most of this chapter focuses on unipolar depression in ASD as the more well-studied mood disorder, the chapter also summarizes the small research base on bipolar disorder in the context of ASD. It ends with a call for improved screening, assessment, and evidence-based treatment options to address this significant public health problem in this special population.

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