TY  - JOUR
AB  - Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the SCN1A gene encoding the voltage-gated sodium channel α subunit Nav1.1. Multiple seizure types, cognitive deterioration, behavioral disturbances, ataxia, and sudden unexpected death associated with epilepsy are a hallmark of the disease. Recently approved antiseizure medications such as fenfluramine and cannabidiol have been shown to reduce seizure burden. However, patients with Dravet syndrome are still medically refractory in the majority of cases, and there is a high demand for new therapies aiming to improve behavioral and cognitive outcome. Drug-repurposing approaches for SCN1A-related Dravet syndrome are currently under investigation (i.e., lorcaserin, clemizole, and ataluren). New therapeutic concepts also arise from the field of precision medicine by upregulating functional SCN1A or by activating Nav1.1. These include antisense nucleotides directed against the nonproductive transcript of SCN1A with the poison exon 20N and against an inhibitory noncoding antisense RNA of SCN1A. Gene therapy approaches such as adeno-associated virus-based upregulation of SCN1A using a transcriptional activator (ETX101) or CRISPR/dCas technologies show promising results in preclinical studies. Although these new treatment concepts still need further clinical research, they offer great potential for precise and disease modifying treatment of Dravet syndrome.
AU  - Lersch, R.*
AU  - Jannadi, R.*
AU  - Grosse, L.*
AU  - Wagner, M.
AU  - Schneider, M.F.*
AU  - von Stülpnagel, C.*
AU  - Heinen, F.*
AU  - Potschka, H.*
AU  - Borggraefe, I.*
C1  - 64795
C2  - 52494
TI  - Targeted molecular strategies for genetic neurodevelopmental disorders: Emerging lessons from dravet syndrome.
JO  - Neuroscientist
PY  - 2022
SN  - 1073-8584
ER  - 

TY  - JOUR
AB  - Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer’s disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer’s disease.
AU  - Ovsepian, S.V.
AU  - O'Leary, V.B.*
AU  - Zaborszky, L.*
AU  - Ntziachristos, V.
AU  - Dolly, J.O.*
C1  - 54042
C2  - 45213
SP  - 288-297
TI  - Amyloid plaques of Alzheimer’s disease as hotspots of glutamatergic activity.
JO  - Neuroscientist
VL  - 25
IS  - 4
PY  - 2018
SN  - 1073-8584
ER  - 

TY  - JOUR
AB  - Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease.
AU  - Ovsepian, S.V.*
AU  - O'Leary, V.B.
AU  - Zaborszky, L.*
C1  - 44921
C2  - 37114
CY  - Thousand Oaks
SP  - 238-251
TI  - Cholinergic mechanisms in the cerebral cortex: Beyond synaptic transmission.
JO  - Neuroscientist
VL  - 22
IS  - 3
PB  - Sage Publications Inc
PY  - 2016
SN  - 1073-8584
ER  -