Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer's disease.
Abstract Alzheimer's disease (AD) leads to cerebral accumulation of insoluble amyloid-β plaques causing synaptic dysfunction and neuronal death. Neurons rely on astrocyte-derived glutamine for replenishment of the amino acid neurotransmitter pools. Perturbations of astrocyte glutamine synthesis have been described in AD, but whether this functionally affects neuronal neurotransmitter synthesis is not known. Since the synthesis and recycling of neurotransmitter glutamate and GABA are intimately coupled to cellular metabolism, the aim of this study was to provide a functional investigation of neuronal and astro...
Source: Neurobiology of Disease - November 23, 2020 Category: Neurology Authors: Andersen JV, Christensen SK, Westi EW, Diaz-delCastillo M, Tanila H, Schousboe A, Aldana BI, Waagepetersen HS Tags: Neurobiol Dis Source Type: research

Lateral habenula dysfunctions in Tm4sf2-/y mice model for neurodevelopmental disorder.
Abstract Mutations in the TM4SF2 gene, which encodes TSPAN7, cause a severe form of intellectual disability (ID) often comorbid with autism spectrum disorder (ASD). Recently, we found that TM4SF2 loss in mice affects cognition. Here, we report that Tm4sf2-/y mice, beyond an ID-like phenotype, display altered sociability, increased repetitive behaviors, anhedonic- and depressive-like states. Cognition relies on the integration of information from several brain areas. In this context, the lateral habenula (LHb) is strategically positioned to coordinate the brain regions involved in higher cognitive functions. Furthe...
Source: Neurobiology of Disease - November 20, 2020 Category: Neurology Authors: Luca M, Luisa P, Anna L, Sara M, Giorgia G, Silvia B, Mariaelvina S, Maria P Tags: Neurobiol Dis Source Type: research

Neuroimaging and neuropathology studies of X-linked dystonia parkinsonism.
Abstract X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms include the initial appearance of dystonia, followed by parkinsonian traits after 10-15 years. The basal ganglia, particularly the striatum, is an area of focus in XDP neuropathology research, as the striatum shows marked atrophy that correlates with disease progression. Thus, XDP shares features of Parkinson's disease symptomatology, in addition to the genetic predisposition and presence of striatal atrophy resembling Huntington's disease. H...
Source: Neurobiology of Disease - November 20, 2020 Category: Neurology Authors: Arasaratnam CJ, Singh-Bains MK, Waldvogel HJ, Faull RLM Tags: Neurobiol Dis Source Type: research

Glutamate transmission rather than cellular pacemaking propels excitatory-inhibitory resonance for ictogenesis in amygdala.
Abstract Epileptic seizures are automatic, excessive, and synchronized neuronal activities originating from many brain regions especially including the amygdala, the allocortices and neocortices. This may reflect a shared principle for network organization and signaling in these telencephalic structures. In theory, the automaticity of epileptic discharges may stem from spontaneously active "oscillator" neurons equipped with intrinsic pacemaking conductances, or from a group of synaptically-connected collaborating "resonator" neurons. In the basolateral amygdalar (BLA) network of pyramidal-inhib...
Source: Neurobiology of Disease - November 19, 2020 Category: Neurology Authors: Wang GH, Chou P, Hsueh SW, Yang YC, Kuo CC Tags: Neurobiol Dis Source Type: research

Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease.
Abstract Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In th...
Source: Neurobiology of Disease - November 19, 2020 Category: Neurology Authors: Marmion DJ, Rutkowski AA, Chatterjee D, Hiller BM, Werner MH, Bezard E, Kirik D, McCown T, Gray SJ, Kordower JH Tags: Neurobiol Dis Source Type: research

Oligomeric α-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson's disease.
Oligomeric α-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson's disease. Neurobiol Dis. 2020 Nov 17;:105185 Authors: Agliardi C, Meloni M, Guerini FR, Zanzottera M, Bolognesi E, Baglio F, Clerici M Abstract Blood-based biomarkers are needed to be used as easy, reproducible, and non-invasive tools for the diagnosis and prognosis of chronic neurodegenerative disorders including Parkinson's Disease (PD). In PD, aggregated toxic forms of α-Synuclein (α-Syn) accumulate within neurons in the brain and cause neurodegeneration;...
Source: Neurobiology of Disease - November 17, 2020 Category: Neurology Authors: Agliardi C, Meloni M, Guerini FR, Zanzottera M, Bolognesi E, Baglio F, Clerici M Tags: Neurobiol Dis Source Type: research

Bioinformatics analyses show dysregulation of calcium-related genes in Angelman syndrome mouse model.
Abstract BACKGROUND: Angelman syndrome (AS) is a genetic neurodevelopmental disorder caused by the loss of function of the UBE3A protein in the brain. In a previous study, we showed that activity-dependent calcium dynamics in hippocampal CA1 pyramidal neurons of AS mice is compromised, and its normalization rescues the hippocampal-dependent deficits. Therefore, we expected that the expression profiles of calcium-related genes would be altered in AS mice hippocampi. METHODS: We analyzed mRNA sequencing data from AS model mice and WT controls in light of the newly published CaGeDB database of calcium-related ge...
Source: Neurobiology of Disease - November 16, 2020 Category: Neurology Authors: Panov J, Kaphzan H Tags: Neurobiol Dis Source Type: research

Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study.
CONCLUSION: These findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear. PMID: 33207277 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - November 15, 2020 Category: Neurology Authors: Mathern GW, Bertram EH Tags: Neurobiol Dis Source Type: research

X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder.
Abstract CDKL5 deficiency disorder (CDD) is an infantile epileptic encephalopathy presenting with early-onset seizures, intellectual disability, motor impairment, and autistic features. The disorder has been linked to mutations in the X-linked CDKL5, and mouse models of the disease recapitulate several aspects of CDD symptomology, including learning and memory impairments, motor deficits, and autistic-like features. Although early-onset epilepsy is one of the hallmark features of CDD, evidence of spontaneous seizure activity has only recently been described in Cdkl5-deficient heterozygous female mice, but the etio...
Source: Neurobiology of Disease - November 13, 2020 Category: Neurology Authors: Terzic B, Cui Y, Edmondson AC, Tang S, Sarmiento N, Zaitseva D, Marsh ED, Coulter DA, Zhou Z Tags: Neurobiol Dis Source Type: research

Ethanol-mediated alterations in oligodendrocyte differentiation in the developing brain.
CONCLUSION: Prenatal EtOH exposure is associated with excessive OL apoptosis and/or delayed OL maturation in human fetal brain. This is accompanied by markedly dysregulated expression of several chemokines and cytokines, in a pattern predictive of increased OL cytotoxicity and reduced OL differentiation. These findings are consistent with findings in animal models of FAS. PMID: 33189883 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - November 12, 2020 Category: Neurology Authors: Darbinian N, Darbinyan A, Merabova N, Bajwa A, Tatevosian G, Martirosyan D, Zhao H, Selzer ME, Goetzl L Tags: Neurobiol Dis Source Type: research

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.
Abstract Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession of the variant M, et al.lele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect...
Source: Neurobiology of Disease - November 11, 2020 Category: Neurology Authors: Mercado NM, Stancati JA, Sortwell CE, Mueller RL, Boezwinkle SA, Duffy MF, Fischer DL, Sandoval IM, Manfredsson FP, Collier TJ, Steece-Collier K Tags: Neurobiol Dis Source Type: research

Epigenetic principles underlying epileptogenesis and epilepsy syndromes.
Abstract Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. Driving this aberrant cellular function are large scale changes in gene expression and gene expression regulation. Recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome. Epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. ...
Source: Neurobiology of Disease - November 9, 2020 Category: Neurology Authors: Conboy K, Henshall DC, Brennan GP Tags: Neurobiol Dis Source Type: research

Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity.
Abstract Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition. The hallmark of LD is the accumulation of aberrant glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Impeding glycogen synthesis from early embryonic stages by genetic suppression of glycogen synthase (MGS) in an animal model of LD prevents LB formation and ultimately the pathological manifestations of LD thereby indicating that LBs are responsible for the pathophysiology of the disease. However, it is not clear whether eliminating glycogen synthesis in an adult animal after LBs have already formed w...
Source: Neurobiology of Disease - November 7, 2020 Category: Neurology Authors: Varea O, Duran J, Aguilera M, Prats N, Guinovart JJ Tags: Neurobiol Dis Source Type: research

PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
Pizcueta P Abstract Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron‑sulfur clusters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-acti...
Source: Neurobiology of Disease - November 7, 2020 Category: Neurology Authors: Rodríguez-Pascau L, Britti E, Calap-Quintana P, Dong YN, Vergara C, Delaspre F, Medina M, Tamarit J, Pallardó FV, Gonzalez-Cabo P, Ros J, Lynch DR, Martinell M, Pizcueta P Tags: Neurobiol Dis Source Type: research

Epigenetic regulation of neural lineage elaboration: Implications for therapeutic reprogramming.
z M Abstract The vulnerability of the mammalian brain is mainly due to its limited ability to generate new neurons once fully matured. Direct conversion of non-neuronal cells to neurons opens up a new avenue for therapeutic intervention and has made great strides also for in vivo applications in the injured brain. These great achievements raise the issue of adequate identity and chromatin hallmarks of the induced neurons. This may be particularly important, as aberrant epigenetic settings may reveal their adverse effects only in certain brain activity states. Therefore, we review here the knowledge about epigeneti...
Source: Neurobiology of Disease - November 7, 2020 Category: Neurology Authors: Stricker SH, Götz M Tags: Neurobiol Dis Source Type: research

Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon.
Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon. Neurobiol Dis. 2020 Nov 07;:105164 Authors: Zorgniotti A, Ditamo Y, Arce CA, Bisig CG Abstract L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstra...
Source: Neurobiology of Disease - November 7, 2020 Category: Neurology Authors: Zorgniotti A, Ditamo Y, Arce CA, Bisig CG Tags: Neurobiol Dis Source Type: research

What are activated and reactive glia and what is their role in neurodegeneration?
Abstract In injury and disease, microglia and astrocytes - two major non-neuronal cell types in the central nervous system (CNS) - undergo morphological, transcriptional, and functional changes, which can underlie pathogenesis and dysfunction of the CNS. Microglia, the brain's tissue resident parenchymal macrophages, are described as becoming "activated" as they deftly change their production of different inflammatory mediators, alter the surveillance behavior of their cellular protrusions, and differentially influence the function of astrocytes. For their part, astrocytes - the most abundant glial cell ...
Source: Neurobiology of Disease - November 7, 2020 Category: Neurology Authors: Bennett ML, Viaene AN Tags: Neurobiol Dis Source Type: research

Autoimmunity and NMDA receptor in brain disorders: Where do we stand?
Abstract Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated great hope to shed new light on the molecular mechanisms underpinning neurological and psychiatric conditions. Among these autoimmune encephalitis, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the anti-NMDAR encephalitis, has provided some key information on how complex neuropsychiatric symptoms can be caused by a deficit in NMDAR signalling. Yet, NMDAR-Abs have also been detected in severa...
Source: Neurobiology of Disease - November 6, 2020 Category: Neurology Authors: Hunter D, Jamet Z, Groc L Tags: Neurobiol Dis Source Type: research

Deep brain stimulation by optimized stimulators in a phenotypic model of dystonia: Effects of different frequencies.
chter A Abstract Deep brain stimulation (DBS) of the globus pallidus internus (GPi, entopeduncular nucleus, EPN, in rodents) has become important for the treatment of generalized dystonia, a severe and often intractable movement disorder. It is unclear if lower frequencies of GPi-DBS or stimulations of the subthalamic nucleus (STN) are of advantage. In the present study, the main objective was to examined the effects of bilateral EPN-DBS at different frequencies (130 Hz, 40 Hz, 15 Hz) on the severity of dystonia in the dtsz mutant hamster. In addition, STN stimulations were done at a frequency, proven to be ...
Source: Neurobiology of Disease - November 6, 2020 Category: Neurology Authors: Paap M, Perl S, Lüttig A, Plocksties F, Niemann C, Timmermann D, Bahls C, van Rienen U, Franz D, Zwar M, Rohde M, Köhling R, Richter A Tags: Neurobiol Dis Source Type: research

Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice.
In this study, we injected AAV to express Ca2+ indicator in layer II/III motor cortex neurons and measured neuronal Ca2+ activity by two photon imaging in awake transgenic JNPL3 tauopathy and wild-type mice. Various biochemical measurements were conducted in postmortem mouse brains for mechanistic insight and a group of animals received two intravenous injections of a tau monoclonal antibody spaced by four days to test whether the Ca2+ dyshomeostasis was related to pathological tau protein. Under running conditions, we found abnormal neuronal Ca2+ activity in tauopathy mice compared to age-matched wild-type mice with highe...
Source: Neurobiology of Disease - November 6, 2020 Category: Neurology Authors: Wu Q, Bai Y, Li W, Congdon EE, Liu W, Lin Y, Ji C, Gan WB, Sigurdsson EM Tags: Neurobiol Dis Source Type: research

The brain and behavioral correlates of motor-related analgesia (MRA).
Abstract The human motor system has the capacity to act as an internal form of analgesia. Since the discovery of the potential influence of motor systems on analgesia in rodent models, clinical applications of targeting the motor system for analgesia have been implemented. However, a neurobiological basis for motor activation's effects on analgesia is not well defined. Motor-related analgesia (MRA) is a phenomenon wherein a decrease in pain symptoms can be achieved through either indirect or direct activation of the motor axis. To date, research has focused on (a) evaluating the pain-motor interaction as one focus...
Source: Neurobiology of Disease - November 3, 2020 Category: Neurology Authors: Holmes SA, Kim A, Borsook D Tags: Neurobiol Dis Source Type: research

Neocortical in vivo focal and spreading potassium responses and the influence of astrocytic gap junctional coupling.
Abstract Raised extracellular potassium ion (K+) concentration is associated with several disorders including migraine, stroke, neurotrauma and epilepsy. K+ spatial buffering is a well-known mechanism for extracellular K+ regulation/distribution. Astrocytic gap junction-mediated buffering is a controversial candidate for K+ spatial buffering. To further investigate the existence of a K+ spatial buffering and to assess the involvement of astrocytic gap junctional coupling in K+ redistribution, we hypothesized that neocortical K+ and concomitant spreading depolarization (SD)-like responses are controlled by powerful...
Source: Neurobiology of Disease - November 2, 2020 Category: Neurology Authors: EbrahimAmini A, Bazzigaluppi P, Aquilino MS, Stefanovic B, Carlen PL Tags: Neurobiol Dis Source Type: research

Primary motor cortex in Parkinson's disease: Functional changes and opportunities for neurostimulation.
Abstract Movement abnormalities of Parkinson's disease (PD) arise from disordered neural activity in multiple interconnected brain structures. The planning and execution of movement requires recruitment of a heterogeneous collection of pyramidal projection neurons in the primary motor cortex (M1). The neural representations of movement in M1 single-cell and field potential recordings are directly and indirectly influenced by the midbrain dopaminergic neurons that degenerate in PD. This review examines M1 functional alterations in PD as uncovered by electrophysiological recordings and neurostimulation studies in pa...
Source: Neurobiology of Disease - November 2, 2020 Category: Neurology Authors: Underwood CF, Parr-Brownlie LC Tags: Neurobiol Dis Source Type: research

Lessons learned from CHMP2B, implications for frontotemporal dementia and amyotrophic lateral sclerosis.
Abstract Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases with clinical, genetic and pathological overlap. As such, they are commonly regarded as a single spectrum disorder, with pure FTD and pure ALS representing distinct ends of a continuum. Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across the FTD-ALS spectrum. These pathways are, in part, mediated by CHMP2B, a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Here we review how ALS and FTD disease causing ...
Source: Neurobiology of Disease - October 31, 2020 Category: Neurology Authors: Ugbode C, West RJH Tags: Neurobiol Dis Source Type: research

Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome.
Abstract OBJECTIVE: To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS). METHODS: We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise. RESULTS: Core body temperatures of WT and DS mice were similar during baseline. After 15 mins ...
Source: Neurobiology of Disease - October 31, 2020 Category: Neurology Authors: Sahai N, Bard AM, Devinsky O, Kalume F Tags: Neurobiol Dis Source Type: research

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine.
Abstract Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia - an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavior...
Source: Neurobiology of Disease - October 28, 2020 Category: Neurology Authors: Greco R, Demartini C, Zanaboni A, Casini I, De Icco R, Reggiani A, Misto A, Piomelli D, Tassorelli C Tags: Neurobiol Dis Source Type: research

Behavioral, axonal, and proteomic alterations following repeated mild traumatic brain injury: Novel insights using a clinically relevant rat model.
Abstract A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis ...
Source: Neurobiology of Disease - October 27, 2020 Category: Neurology Authors: Pham L, Wright DK, O'Brien WT, Bain J, Huang C, Sun M, Casillas-Espinosa PM, Shah AD, Schittenhelm RB, Sobey CG, Brady RD, O'Brien TJ, Mychasiuk R, Shultz SR, McDonald SJ Tags: Neurobiol Dis Source Type: research

Epigenetic regulators of neuronal ferroptosis identify novel therapeutics for neurological diseases: HDACs, transglutaminases, and HIF prolyl hydroxylases.
Abstract A major thrust of our laboratory has been to identify how physiological stress is transduced into transcriptional responses that feed back to overcome the inciting stress or its consequences, thereby fostering survival and repair. To this end, we have adopted the use of an in vitro model of ferroptosis, a caspase-independent, but iron-dependent form of cell death (Dixon et al., 2012; Ratan, 2020). In this review, we highlight three distinct epigenetic targets that have evolved from our studies and which have been validated in vivo studies. In the first section, we discuss our studies of broad, pan-selecti...
Source: Neurobiology of Disease - October 27, 2020 Category: Neurology Authors: Rroji O, Kumar A, Karuppagounder SS, Ratan RR Tags: Neurobiol Dis Source Type: research

LAR inhibitory peptide promotes recovery of diaphragm function and multiple forms of respiratory neural circuit plasticity after cervical spinal cord injury.
Abstract Chondroitin sulfate proteoglycans (CSPGs), up-regulated in and around the lesion after traumatic spinal cord injury (SCI), are key extracellular matrix inhibitory molecules that limit axon growth and consequent recovery of function. CSPG-mediated inhibition occurs via interactions with axonal receptors, including leukocyte common antigen- related (LAR) phosphatase. We tested the effects of a novel LAR inhibitory peptide in rats after hemisection at cervical level 2, a SCI model in which bulbospinal inspiratory neural circuitry originating in the medullary rostral ventral respiratory group (rVRG) becomes d...
Source: Neurobiology of Disease - October 27, 2020 Category: Neurology Authors: Cheng L, Sami A, Ghosh B, Urban MW, Heinsinger NM, Liang SS, Smith GM, Wright MC, Li S, Lepore AC Tags: Neurobiol Dis Source Type: research

DNA damage and repair following traumatic brain injury.
Abstract Traumatic brain injury (TBI) is known to promote significant DNA damage irrespective of age, sex, and species. Chemical as well as structural DNA modification start within minutes and persist for days after TBI. Although several DNA repair pathways are induced following TBI, the simultaneous downregulation of some of the genes and proteins of these pathways leads to an aberrant overall DNA repair process. In many instances, DNA damages escape even the most robust repair mechanisms, especially when the repair process becomes overwhelmed or becomes inefficient by severe or repeated injuries. The persisting ...
Source: Neurobiology of Disease - October 27, 2020 Category: Neurology Authors: Davis CK, Vemuganti R Tags: Neurobiol Dis Source Type: research

Epigenetic mechanisms underlying enhancer modulation of neuronal identity, neuronal activity and neurodegeneration.
Abstract Neurodegenerative diseases, including Huntington's disease (HD) and Alzheimer's disease (AD), are progressive conditions characterized by selective, disease-dependent loss of neuronal regions and/or subpopulations. Neuronal loss is preceded by a long period of neuronal dysfunction, during which glial cells also undergo major changes, including neuroinflammatory response. Those dramatic changes affecting both neuronal and glial cells associate with epigenetic and transcriptional dysregulations, characterized by defined cell-type-specific signatures. Notably, increasing studies support the view that altered...
Source: Neurobiology of Disease - October 27, 2020 Category: Neurology Authors: Vida RA, Awada A, Boutillier AL, Merienne K Tags: Neurobiol Dis Source Type: research

Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.
Abstract Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aβ1-42 protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aβ exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of th...
Source: Neurobiology of Disease - October 26, 2020 Category: Neurology Authors: Simons ES, Smith MA, Dengler-Crish CM, Crish SD Tags: Neurobiol Dis Source Type: research

Deregulation of signalling in genetic conditions affecting the lysosomal metabolism of cholesterol and galactosyl-sphingolipids.
Abstract The role of lipids in neuroglial function is gaining momentum in part due to a better understanding of how many lipid species contribute to key cellular signalling pathways at the membrane level. The description of lipid rafts as membrane domains composed by defined classes of lipids such as cholesterol and sphingolipids has greatly helped in our understanding of how cellular signalling can be regulated and compartmentalized in neurons and glial cells. Genetic conditions affecting the metabolism of these lipids greatly impact on how some of these signalling pathways work, providing a context to understand...
Source: Neurobiology of Disease - October 17, 2020 Category: Neurology Authors: Gowrishankar S, Cologna SM, Givogri MI, Bongarzone ER Tags: Neurobiol Dis Source Type: research

Molecular mechanisms of psychiatric diseases.
Abstract For most psychiatric diseases, pathogenetic concepts as well as paradigms underlying neuropsychopharmacologic approaches currently revolve around neurotransmitters such as dopamine, serotonin, and norepinephrine. However, despite the fact that several generations of neurotransmitter-based psychotropics including atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are available, the efficacy of these medications is limited, and relapse rates in psychiatric diseases are relatively high, indicating potential involvement of other pathogenetic path...
Source: Neurobiology of Disease - October 17, 2020 Category: Neurology Authors: Blokhin IO, Khorkova O, Saveanu RV, Wahlestedt C Tags: Neurobiol Dis Source Type: research

The relation between tau pathology and granulovacuolar degeneration of neurons.
r C Abstract Neurofibrillary tangles arising from aggregated microtubule-associated protein tau occur in aged brains and are hallmarks of neurodegenerative diseases. A subset of neurons containing aggregated tau displays granulovacuolar degeneration (GVD) that is characterized by membrane-bound cytoplasmic vacuoles, each containing an electron-dense granule (GVB). Tau pathology induces GVBs in experimental models, but GVD does not generally follow tau pathology in the human brain. The entorhinal cortex, DRN, and LC are among the regions that display pathological changes of tau earliest, whereas neurons with GVBs o...
Source: Neurobiology of Disease - October 15, 2020 Category: Neurology Authors: Puladi B, Dinekov M, Arzberger T, Taubert M, Köhler C Tags: Neurobiol Dis Source Type: research

RUES2 hESCs exhibit MGE-biased neuronal differentiation and muHTT-dependent defective specification hinting at SP1.
Abstract RUES2 cell lines represent the first collection of isogenic human embryonic stem cells (hESCs) carrying different pathological CAG lengths in the HTT gene. However, their neuronal differentiation potential has yet to be thoroughly evaluated. Here, we report that RUES2 during ventral telencephalic differentiation is biased towards medial ganglionic eminence (MGE). We also show that HD-RUES2 cells exhibit an altered MGE transcriptional signature in addition to recapitulating known HD phenotypes, with reduced expression of the neurodevelopmental regulators NEUROD1 and BDNF and increased cleavage of synaptica...
Source: Neurobiology of Disease - October 13, 2020 Category: Neurology Authors: Conforti P, Besusso D, Brocchetti S, Campus I, Cappadona C, Galimberti M, Laporta A, Iennaco R, Rossi RL, Dickinson VB, Cattaneo E Tags: Neurobiol Dis Source Type: research

The epitranscriptome in stem cell biology and neural development.
Abstract The blossoming field of epitranscriptomics has recently garnered attention across many fields by findings that chemical modifications on RNA have immense biological consequences. Methylation of nucleotides in RNA, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), and 5-methylcytosine (m5C) and isomerization of uracil to pseudouridine (Ψ), have the potential to alter RNA processing events and contribute to developmental processes and different diseases. Though the abundance and roles of some RNA modifications remain contentious, the epitranscriptome is thought ...
Source: Neurobiology of Disease - October 13, 2020 Category: Neurology Authors: Vissers C, Sinha A, Ming GL, Song H Tags: Neurobiol Dis Source Type: research

TDP-43 and tau oligomers in Alzheimer's disease, amyotrophic lateral sclerosis, and frontotemporal dementia.
Abstract Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplas...
Source: Neurobiology of Disease - October 13, 2020 Category: Neurology Authors: Montalbano M, McAllen S, Cascio FL, Sengupta U, Garcia S, Bhatt N, Ellsworth A, Heidelman EA, Johnson OD, Doskocil S, Kayed R Tags: Neurobiol Dis Source Type: research

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.
Abstract As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report exp...
Source: Neurobiology of Disease - October 11, 2020 Category: Neurology Authors: Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH Tags: Neurobiol Dis Source Type: research

P2Y1 receptor inhibition rescues impaired synaptic plasticity and astroglial Ca2+-dependent activity in the epileptic hippocampus.
Abstract Epilepsy is characterized by a progressive predisposition to suffer seizures due to neuronal hyperexcitability, and one of its most common co-morbidities is cognitive decline. In animal models of chronic epilepsy, such as kindling, electrically induced seizures impair long-term potentiation (LTP), deteriorating learning and memory performance. Astrocytes are known to actively modulate synaptic plasticity and neuronal excitability through Ca2+-dependent gliotransmitter release. It is unclear, however, if astroglial Ca2+ signaling could contribute to the development of synaptic plasticity alterations in the...
Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Martorell A, Wellmann M, Guiffa F, Fuenzalida M, Bonansco C Tags: Neurobiol Dis Source Type: research

Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2 α signaling leading to a compromised stress response.
In this study we evaluate if five DYT16 substitution mutations alter PKR activation and ISR. Our results indicate that the mutant DYT16 proteins show stronger PACT-PACT interactions and enhanced PKR activation. In DYT16 patient derived lymphoblasts the enhanced PACT-PKR interactions and heightened PKR activation leads to a dysregulation of ISR and increased apoptosis. More importantly, this enhanced sensitivity to ER stress can be rescued by luteolin, which disrupts PACT-PKR interactions. Our results not only demonstrate the impact of DYT16 mutations on regulation of ISR and DYT16 etiology but indicate that therapeutic int...
Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Burnett SB, Vaughn LS, Sharma N, Kulkarni R, Patel RC Tags: Neurobiol Dis Source Type: research

Inclusion of African American/black adults in a pilot brain proteomics study of Alzheimer's disease.
Abstract Alzheimer's disease (AD) disproportionately affects certain racial and ethnic subgroups, such as African American/Black and Hispanic adults. Genetic, comorbid, and socioeconomic risk factors contribute to this disparity; however, the molecular contributions have been largely unexplored. Herein, we conducted a pilot proteomics study of postmortem brains from African American/Black and non-Hispanic White adults neuropathologically diagnosed with AD compared to closely-matched cognitively normal individuals. Examination of hippocampus, inferior parietal lobule, and globus pallidus regions using quantitative ...
Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Stepler KE, Mahoney ER, Kofler J, Hohman TJ, Lopez OL, Robinson RAS Tags: Neurobiol Dis Source Type: research

SUMOylation of spastin promotes the internalization of GluA1 and regulates dendritic spine morphology by targeting microtubule dynamics.
Abstract Dendritic spines are specialized structures involved in neuronal processes on which excitatory synaptic contact occurs. The microtubule cytoskeleton is vital for maintaining spine morphology and mature synapses. Spastin is related to microtubule-severing proteases and is involved in synaptic bouton formation. However, it is not yet known if spastin can be modified by Small Ubiquitin-like Modifier (SUMO) or how this modification regulates dendritic spines. Spastin was shown to be SUMOylated at K427, and its deSUMOylation promoted microtubule stability. In addition, SUMOylation of spastin was shown to affec...
Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Ji ZS, Liu QL, Zhang JF, Yang YH, Li J, Zhang GW, Tan MH, Lin HS, Guo GQ Tags: Neurobiol Dis Source Type: research

Adenosine A2A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome.
;R, Cunha RA, Canas PM Abstract Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited Ube3a neuronal protein, whose main features comprise severe intellectual disabilities and motor impairments. Previous studies with the Ube3am-/p+ mouse model of AS revealed deficits in synaptic plasticity and memory. Since adenosine A2A receptors (A2AR) are powerful modulators of aberrant synaptic plasticity and A2AR blockade prevents memory dysfunction in various brain diseases, we tested if A2AR could control deficits of memory and hippocampal synaptic plasticity in AS. W...
Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Moreira-de-Sá A, Gonçalves FQ, Lopes JP, Silva HB, Tomé ÂR, Cunha RA, Canas PM Tags: Neurobiol Dis Source Type: research

Gait variability is linked to the atrophy of the Nucleus Basalis of Meynert and is resistant to STN DBS in Parkinson's disease.
Abstract Parkinson's disease (PD) is a systemic brain disorder where the cortical cholinergic network begins to degenerate early in the disease process. Readily accessible, quantitative, and specific behavioral markers of the cortical cholinergic network are lacking. Although degeneration of the dopaminergic network may be responsible for deficits in cardinal motor signs, the control of gait is a complex process and control of higher-order aspects of gait, such as gait variability, may be influenced by cognitive processes attributed to cholinergic networks. We investigated whether swing time variability, a metric ...
Source: Neurobiology of Disease - October 9, 2020 Category: Neurology Authors: Wilkins KB, Parker JE, Bronte-Stewart HM Tags: Neurobiol Dis Source Type: research

Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome.
Abstract Fragile X syndrome (FXS), a neurodevelopmental disorder with autistic features, is caused by the loss of the fragile X mental retardation protein. Sex-specific differences in the clinical profile have been observed in FXS patients, but few studies have directly compared males and females in rodent models of FXS. To address this, we performed electroencephalography (EEG) recordings and a battery of autism-related behavioral tasks on juvenile and young adult Fmr1 knockout (KO) rats. EEG analysis demonstrated that compared to wild-type, male Fmr1 KO rats showed an increase in gamma frequency band power in th...
Source: Neurobiology of Disease - October 5, 2020 Category: Neurology Authors: Wong H, Hooper AWM, Niibori Y, Lee SJ, Hategan LA, Zhang L, Karumuthil-Melethil S, Till SM, Kind PC, Danos O, Bruder JT, Hampson DR Tags: Neurobiol Dis Source Type: research

IP3R-mediated intra-axonal Ca2+ release contributes to secondary axonal degeneration following contusive spinal cord injury.
Abstract Secondary axonal loss contributes to the persistent functional disability following trauma. Consequently, preserving axons following spinal cord injury (SCI) is a major therapeutic goal to improve neurological outcome; however, the complex molecular mechanisms that mediate secondary axonal degeneration remain unclear. We previously showed that IP3R-mediated Ca2+ release contributes to axonal dieback and axonal loss following an ex vivo laser-induced SCI. Nevertheless, targeting IP3R in a clinically relevant in vivo model of SCI and determining its contribution to secondary axonal degeneration has yet to b...
Source: Neurobiology of Disease - September 30, 2020 Category: Neurology Authors: Orem BC, Rajaee A, Stirling DP Tags: Neurobiol Dis Source Type: research

Transitions between neocortical seizure and non-seizure-like states and their association with presynaptic glutamate release.
Abstract The transition between seizure and non-seizure states in neocortical epileptic networks is governed by distinct underlying dynamical processes. Based on the gamma distribution of seizure and inter-seizure durations, over time, seizures are highly likely to self-terminate; whereas, inter-seizure durations have a low chance of transitioning back into a seizure state. Yet, the chance of a state transition could be formed by multiple overlapping, unknown synaptic mechanisms. To identify the relationship between the underlying synaptic mechanisms and the chance of seizure-state transitions, we analyzed the ske...
Source: Neurobiology of Disease - September 29, 2020 Category: Neurology Authors: Breton VL, Dufour S, Chinvarun Y, Del Campo JM, Bardakjian BL, Carlen PL Tags: Neurobiol Dis Source Type: research

Nr2e3 functional domain ablation by CRISPR-Cas9D10Aidentifies a new isoform and generates retinitis pigmentosa and enhanced S-cone syndrome models.
illa P, Marfany G Abstract Mutations in NR2E3 cause retinitis pigmentosa (RP) and enhanced S-cone syndrome (ESCS) in humans. This gene produces a large isoform encoded in 8 exons and a previously unreported shorter isoform of 7 exons, whose function is unknown. We generated two mouse models by targeting exon 8 of Nr2e3 using CRISPR/Cas9-D10A nickase. Allele Δ27 is an in-frame deletion of 27 bp that ablates the dimerization domain H10, whereas allele ΔE8 (full deletion of exon 8) produces only the short isoform, which lacks the C-terminal part of the ligand binding domain (LBD) that encodes both H10 a...
Source: Neurobiology of Disease - September 28, 2020 Category: Neurology Authors: Aísa-Marín I, López-Iniesta MJ, Milla S, Lillo J, Navarro G, de la Villa P, Marfany G Tags: Neurobiol Dis Source Type: research

Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats.
Abstract The balance of excitatory and inhibitory neurons in the central nervous system is critical for maintaining brain function and sevoflurane, a general anesthetic and an GABA receptor modulator, may change the balance of excitatory and inhibitory neurons in the cortex during early brain development. Herein, we investigated whether prenatal sevoflurane exposure (PSE) disturbs cortical neuronal development and brain function. Pregnant rats at the gestational day 14.5 were subjected to sevoflurane exposure at 3.0% for 3 h and their offspring were studied thereafter. We found a significant increase of parvalbu...
Source: Neurobiology of Disease - September 28, 2020 Category: Neurology Authors: Zhao T, Chen Y, Sun Z, Shi Z, Qin J, Lu J, Li C, Ma D, Zhou L, Song X Tags: Neurobiol Dis Source Type: research