Increased levels of rictor prevent mutant huntingtin-induced neuronal degeneration

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin

Temporal dynamics and neuronal specificity of Grin3a expression in the mouse forebrain

GluN3A subunits endow N-Methyl-D-Aspartate receptors (NMDARs) with unique biophysical, trafficking, and signaling properties. GluN3A-NMDARs are typically expressed during postnatal development, when they are thought to gate the refinement of neural circuits by inhibiting synapse maturation, and stabilization. Recent work suggests that GluN3A also operates in adult brains to control a variety of behaviors, yet a full spatiotemporal characterization of GluN3A expression is lacking. Here, we conducted a systematic analysis of Grin3a (gene encoding mouse GluN3A) mRNA expression in the mouse brain by combining high-sensitivity colorimetric and fluorescence in situ hybridization with labeling for neuronal subtypes. We find that, while Grin3a mRNA expression peaks postnatally, significant levels are retained into adulthood in specific brain regions such as the amygdala, medial habenula, association cortices, and high-order thalamic nuclei. The time-course of emergence and down-regulation of Grin3a expression varies across brain region, cortical layer of residence, and sensory modality, in a pattern that correlates with previously reported hierarchical gradients of brain maturation and functional specialization. Grin3a is expressed in both excitatory and inhibitory neurons, with strong mRNA levels being a distinguishing feature of somatostatin interneurons. Our study provides a comprehensive map of Grin3a distribution across the murine lifespan and paves the way for dissecting the diverse functions of GluN3A in health and disease. circuit refinement, excitatory glycine receptors, high-order thalamus, neocortical maturation, somatostatin interneuron

Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models

Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression

Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs

Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD

Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes

<div><p>Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. <i>In vivo</i>, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.</p></div

The role of the boundaries in the organisation of geographical space in Latvia

ANOTĀCIJA Mūsdienu globalizācijas procesos valstu politisko robežu nozīmes samazināšanās apstākļos pieaug interese par robežu pētījumiem dažādos mērogos – robežas kļūst būtiskas reģionālā un lokālā līmenī. Latvijā pēdējā desmitgadē ir notikuši aktīvi teritoriālās politikas procesi veidojot jaunu administratīvu, pārvaldes struktūru, telpiski bāzētus attīstības instrumentus, kur nozīmīgu vietu ieņem robežas. Līdzšinējie Pētījumi, kas saistīti ar teritorijām Latvijā, neskata robežu kā pētījumu objektu. Robeža kā domāšanas un telpiskās rīcības produkts izpaužas teritoriālajās politikās kā līdzeklis un atspoguļojums. Pētījuma pieeja pamatojas uz ģeogrāfiskās ontoloģijas pētījumiem, kas Latvijā nav pazīstami un izmantoti. Darba lietotā pieeja skata robežas kā attiecību telpu, kas veidojas plānošanas procesā caur privātā – publiskā attiecību prizmu Pierīgas un Piekrastes robežtelpās. Robežas izpaužas kā juridisks, fizisks un sociālo attiecību fenomens, kas ir robežtelpu analīzes fokusi. Darbs balstās uz plānošanas dokumentu, kartogrāfiskās informācijas analīzi, intervijām, teritorijas apsekojumiem, foto fiksāciju un rezultātu interpretāciju. Darbā analizēta robežu kā fenomena, domāšanas produkta un rīcību instrumenta loma tās ietekmēs. Ir izstrādāta un aprobēta pieeja robežu pētīšanai, kas balstās uz robežtelpu konceptu teritoriālās praksēs Latvijā. Darbā izvērtēta robežu loma un izmantošanas iespējas teritorijas apsaimniekošanā un plānošanā. Darbu veido piecas daļas. Pirmajā daļā analizēti robežu pētījumi no ontoloģijas, funkcionālā un lietišķā aspekta un pamatota darbā lietoto pieeja. Otrā daļa pamato darbā lietotās metodes. Trešā daļa analizē formālās, funkcionālās un attiecību robežas un to darbību Pierīgas un Piekrastes robežtelpās dažādu privātā – publiskā attiecību gadījumos. Ceturtā daļa apkopo ieteikumus, priekšlikumus un diskusiju jautājumus. Piektā sadaļa apkopo atziņas un secinājumus.ANNOTATION In current globalisation and in the situation of the diminishing role of state boundaries at the same time there is an increasing interest about boundary studies on different scales, particularly at the regional and local level. The last decade has been characterized by active territorial policies in Latvia, creating a new administrative and governance structure and spatial development instruments where boundaries play an important role. Researches in connection with territories do not consider boundaries as an object of research in Latvia. A Boundary as a cognitive and spatial performing product represents in territorial policies as a tool and a reflection. The research approach has been based on ontological studies, which are new and not used in Latvia. With the help of the research approach used in the doctoral thesis boundaries have been looked as relation space which is formed in planning processes through the prism of public-private relations in Riga suburban and Coastal border spaces. A Boundary as a juridical, physical and social relational phenomenon is a focal point of study. The thesis has been based on the analysis and interpretation of planning documents, cartographic information, interviews, field research and photo fixation. The doctoral thesis analyse the role of boundaries as a phenomenon, a cognitive product and an instrument of spatial action in their impacts. The research approach based on the Border space concept has been elaborated and approbated in territorial practices in Latvia. The thesis analyse the role and the possibilities of application of boundaries in land management and planning. The doctoral thesis consists of five parts. Part 1 includes boundaries studies from ontological, functional and applied aspects and substitute approach used in the work. Part 2 explains the methods used in the work. Part 3 analyses formal, functional and relational boundaries and their role in Suburban and Coastal border spaces in different cases of public - private relations. Part 4 summarizes suggestions, recommendations and discussions. Part 5 includes conclusions