scholarly journals Glutamatergic and GABAergic neurons mediate distinct neurodevelopmental phenotypes of STXBP1 encephalopathy

2021 ◽  
Author(s):  
Joo Hyun Kim ◽  
Wu Chen ◽  
Eugene S Chao ◽  
Hongmei Chen ◽  
Mingshan Xue
Keyword(s):  
Broad Spectrum ◽  
Neurotransmitter Release ◽  
Gabaergic Neurons ◽  
Disease Mechanism ◽  
Gabaergic Neurotransmission ◽  
Epileptic Encephalopathies ◽  
Disease Phenotypes ◽  
Pathogenic Variants ◽  
Distinct Disease ◽  
Inhibitory Signaling

Heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) cause STXBP1 encephalopathy and are among the most frequent causes of developmental and epileptic encephalopathies and intellectual disabilities. STXBP1 is an essential protein for presynaptic neurotransmitter release, and its haploinsufficiency impairs glutamatergic and GABAergic neurotransmission. However, the mechanism underlying the broad spectrum of neurological phenotypes is poorly understood. Here we show that glutamatergic and GABAergic neurons mediate distinct disease features with few overlaps. Glutamatergic and GABAergic neurons-specific Stxbp1 haploinsufficient mice exhibit different subsets of the cognitive and seizure phenotypes observed in the constitutive Stxbp1 haploinsufficient mice. Developmental delay and most of the motor and psychiatric phenotypes are only recapitulated by GABAergic Stxbp1 haploinsufficiency. Thus, the contrasting roles of excitatory and inhibitory signaling in STXBP1 encephalopathy identify GABAergic dysfunction as a main disease mechanism and reveal the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

scholarly journals Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

2021 ◽  
Vol 22 (8) ◽  
pp. 4202
Author(s):  
Carlotta Spagnoli ◽  
Carlo Fusco ◽  
Antonio Percesepe ◽  
Vincenzo Leuzzi ◽  
Francesco Pisani
Keyword(s):  
Movement Disorders ◽  
Time Course ◽  
Neonatal Period ◽  
Age Of Onset ◽  
Brain Mri ◽  
Neonatal Seizure ◽  
Mri Findings ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Neonatal Onset

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

scholarly journals αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0235136
Author(s):  
Sara Morais ◽  
Jorge Oliveira ◽  
Catarina Lau ◽  
Mónica Pereira ◽  
Marta Gonçalves ◽  
...  
Keyword(s):  
Binding Sites ◽  
Autosomal Dominant ◽  
Transmembrane Domain ◽  
Laboratory Data ◽  
Atp Release ◽  
Cytoplasmic Domains ◽  
Pathogenic Variants ◽  
Distinct Disease ◽  
And Function ◽  
First Time

Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

scholarly journals Distinct disease‐sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients

2019 ◽  
Vol 30 (2) ◽  
pp. 345-363 ◽  
Author(s):  
Elisabeth Sanchez‐Mejias ◽  
Cristina Nuñez‐Diaz ◽  
Raquel Sanchez‐Varo ◽  
Angela Gomez‐Arboledas ◽  
Juan Antonio Garcia‐Leon ◽  
...  
Keyword(s):  
Perirhinal Cortex ◽  
Gabaergic Neurons ◽  
Distinct Disease

scholarly journals Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kerstin Ure ◽  
Hui Lu ◽  
Wei Wang ◽  
Aya Ito-Ishida ◽  
Zhenyu Wu ◽  
...  
Keyword(s):  
Social Skills ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Therapeutic Option ◽  
Neurodevelopmental Disorder ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Extended Lifespan ◽  
Inhibitory Signaling

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

scholarly journals A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

2020 ◽  
Vol 20 (2) ◽  
pp. 90-96 ◽  
Author(s):  
Hannah C. Happ ◽  
Gemma L. Carvill
Keyword(s):  
Molecular Diagnosis ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Autosomal Recessive Inheritance ◽  
Small Subset ◽  
Recessive Inheritance ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Genetic Mosaicism ◽  
Genetic Landscape

Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.

scholarly journals Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship

2013 ◽  
Vol 8 (1) ◽  
pp. 159 ◽  
Author(s):  
Simone Sampaolo ◽  
Teresa Esposito ◽  
Olimpia Farina ◽  
Daniela Formicola ◽  
Daria Diodato ◽  
...  
Keyword(s):  
Late Onset ◽  
Disease Phenotypes ◽  
Distinct Disease

scholarly journals Mapping and Identification of GABAergic Neurons in Transgenic Mice Projecting to Cardiac Vagal Neurons in the Nucleus Ambiguus Using Photo-Uncaging

2009 ◽  
Vol 101 (4) ◽  
pp. 1755-1760 ◽  
Author(s):  
J. G. Frank ◽  
H. S. Jameson ◽  
C. Gorini ◽  
D. Mendelowitz
Keyword(s):  
Neural Control ◽  
Gabaergic Neurons ◽  
Nucleus Ambiguus ◽  
Gabaergic Neurotransmission ◽  
Transgenic Mouse Line ◽  
Bötzinger Complex ◽  
Green Florescent Protein ◽  
Caged Glutamate ◽  
The Brain ◽  
Synaptic Responses

The neural control of heart rate is determined primarily by the activity of preganglionic parasympathetic cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA) in the brain stem. GABAergic inputs to CVNs play an essential role in determining the activity of these neurons including a robust inhibition during each inspiratory burst. The origin of GABAergic innervation has yet to be determined however. A transgenic mouse line expressing green florescent protein (GFP) in GABAergic cells was used in conjunction with caged glutamate to identify both clusters and individual GABAergic neurons that evoke inhibitory GABAergic synaptic responses in CVNs. Transverse slices were taken with CVNs patch-clamped in the whole cell configuration. Sections containing both the pre-Botzinger complex as well as the calamus scriptorius were divided into ∼90 quadrants, each 200 × 200 μm and were sequentially photostimulated. Inhibitory post synaptic currents (IPSCs) were recorded in CVNs after a 5-ms photostimulation of 50 μM caged glutamate. The four areas that contained GABAergic cells projecting to CVNs were 200 μm medial, 400 μm medial, 200 μm ventral, and 1,200 μm dorsal and 1,000 μm medial to patched CVNs. Once foci of GABAergic cells projecting to CVNs were determined, photostimulation of individual GABAergic neurons was conducted. The results from this study suggest that GABAergic cells located in four specific areas project to CVNs, and that these cells can be individually identified and stimulated using photouncaging to recruit GABAergic neurotransmission to CVNs.

scholarly journals Angiotensin-II modulates GABAergic neurotransmission in the mouse substantia nigra

2021 ◽  
Author(s):  
Maibam R. Singh ◽  
Jozsef Vigh ◽  
Gregory C. Amberg
Keyword(s):  
Angiotensin Ii ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Gabaergic Neurons ◽  
Inhibitory Input ◽  
Ang Ii ◽  
Signaling Mechanism ◽  
Gabaergic Neurotransmission

ABSTRACTGABAergic projections neurons of the substantia nigra reticulata (SNr), through an extensive network of dendritic arbors and axon collaterals, provide robust inhibitory input to neighboring dopaminergic neurons in the substantia nigra compacta (SNc). Angiotensin-II (Ang-II) receptor signaling increases SNc dopaminergic neuronal sensitivity to insult, thus rendering these cells susceptible to dysfunction and destruction. However, the mechanisms by which Ang-II regulates SNc dopaminergic neuronal activity are unclear. Given the complex relationship between SN dopaminergic and GABAergic neurons, we hypothesized that Ang-II could regulate SNc dopaminergic neuronal activity directly and indirectly by modulating SNr GABAergic neurotransmission. Herein, using transgenic mice, slice electrophysiology, and optogenetics, we provide evidence of an AT1 receptor-mediated signaling mechanism in SNr GABAergic neurons where Ang-II suppresses electrically-evoked neuronal output by facilitating postsynaptic GABAA receptors and prolonging the action potential duration. Unexpectedly, Ang-II had no discernable effects on the electrical properties of SNc dopaminergic neurons. Also, and indicating a nonlinear relationship between electrical activity and neuronal output, following phasic photoactivation of SNr GABAergic neurons, Ang-II paradoxically enhanced the feedforward inhibitory input to SNc dopaminergic neurons. In sum, our observations describe an increasingly complex and heterogeneous response of the SN to Ang-II by revealing cell-specific responses and nonlinear effects on intranigral GABAergic neurotransmission. Our data further implicate the renin-angiotensin-system as a functionally relevant neuromodulator in the basal ganglia, thus underscoring a need for additional inquiry.SIGNIFICANCE STATEMENTAngiotensin II (Ang-II) promotes dopamine release in the striatum and, in the substantia nigra compacta (SNc), exacerbates dopaminergic cell loss in animal models of Parkinson’s disease. Despite a potential association with Parkinson’s disease, the effects of Ang-II on neuronal activity in the basal ganglia is unknown. Here we describe a novel AT1 receptor-dependent signaling mechanism in GABAergic projection neurons of the SN reticulata (SNr), a major inhibitory regulator of SNc dopaminergic neurons. Specifically, Ang-II suppresses SNr GABAergic neuronal activity, subsequently altering GABAergic modulation of SNc dopaminergic neurons in a nonlinear fashion. Altogether, our data provide the first indication of Ang-II-dependent modulation of GABAergic neurotransmission in the SN, which could impact output from the basal ganglia in health and disease.

scholarly journals Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Wu Chen ◽  
Zhao-Lin Cai ◽  
Eugene S Chao ◽  
Hongmei Chen ◽  
Colleen M Longley ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Neurotransmitter Release ◽  
De Novo ◽  
Synaptic Proteins ◽  
Synaptic Dysfunction ◽  
Pathogenic Variants ◽  
Cortical Hyperexcitability ◽  
Genes Encoding ◽  
Neurological Features ◽  
Presynaptic Proteins

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, with the majority affecting postsynaptic apparatuses and much fewer in presynaptic proteins. Syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) is an essential component of the presynaptic neurotransmitter release machinery. De novo heterozygous pathogenic variants in STXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeled STXBP1 encephalopathy in mice and found that Stxbp1 haploinsufficiency caused cognitive, psychiatric, and motor dysfunctions, as well as cortical hyperexcitability and seizures. Furthermore, Stxbp1 haploinsufficiency reduced cortical inhibitory neurotransmission via distinct mechanisms from parvalbumin-expressing and somatostatin-expressing interneurons. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate cardinal features of STXBP1 encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.

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