Developing glutamatergic connectivity in the hippocampus : the role of tonically active kainate receptors

The development of glutamatergic transmission in the brain occurs gradually during the first postnatal weeks. During this critical period, nascent synaptic connections are finely tuned to form networks reliably transmitting and processing information. In the hippocampus, kainate receptors (KARs) are heavily expressed during early development and suggested to have an instrumental role in the activity-dependent development of neuronal connectivity. KARs are composed of various combinations of five subunits, GluK1-GluK5. Additional structural and functional diversity of receptors is achieved by alternative splicing and RNA editing of the subunits. The function of KARs differs from the other types of ionotropic glutamate receptors (iGluRs) in two essential respects: first, their primary role is not to mediate but to modulate transmission, and second, KARs use a non-canonical metabotropic signaling mechanism in addition to the classical ionotropic action. The diverse functional roles of KARs are reflected in their highly polarized subcellular localization, which is regulated in a subunit- and cell-specific manner. Despite the increasing number of roles characterized for KARs, their function during development is poorly understood. The aim of this study was to clarify the physiological roles of KARs in the developing glutamatergic connectivity in area CA1 of the rat hippocampus. First, we present a novel, developmentally restricted type of endogenous KAR activity, which has major influence on glutamatergic transmission in the immature hippocampus. During early development, high affinity G-protein-coupled presynaptic KARs are shown to be tonically activated by ambient glutamate to maintain a low probability of glutamate release in a subpopulation of CA3-CA1 synapses. This KAR-mediated presynaptic silencing has a critical impact on the transmission of glutamatergic information; KARs filter out sporadic low-frequency activity and promote transmission during highfrequency bursts representing natural-type of activiy within the immature hippocampal network. Next, we demonstrate that the GluK1c splice variant plays a pivotal role in immature-type KAR activity. The developmental and cell-type specific expression pattern of GluK1c mRNA corresponds to the tonic KAR activity. Furthermore, the presynaptic expression of GluK1c is shown to directly suppress glutamatergic transmission in cell-pairs in vitro and to mimic tonic KAR activity at CA3-CA1 synapses in vivo at a developmental stage when the immature-type KAR activity is already downregulated. Thus, the developmental downregulation of tonic KAR activation can be fully explained by the loss the GluK1c expression in CA3 pyramidal cells. We further show that activity-dependent mechanisms, such as the experimental induction of LTP, can rapidly downregulate tonic KAR activity and switch immature, labile synapses to mature ones. This involves a modification of the receptor per se, leading to the loss of high-affinity KARs. Finally, we show the critical involvement of tonic KAR activity in the formation /stabilization of glutamatergic connections in the hippocampal slice cultures. Mimicking tonic KAR activity by pharmacological activation of GluK1 containing KARs resulted in significant and permanent increase in the number of functional glutamatergic synapses. The essential role of endogenous KAR activity was indicated by the finding that blocking KARs during the period of intense synaptogenesis led to dramatic decrease in glutamatergic connectivity later in development. In summary, the novel findings of this work demonstrate that endogenous KAR activity has crucial role in modulating the glutamatergic transmission and connectivity in the developing hippocampus. This not only broadens our view of the activity-dependent mechanisms underlying the development of synaptic connectivity in the brain, but also provides a basis for understanding the pathophysiological functions of KARs in neurodevelopmental disorders.Kemialliset synapsit välittävät valtaosan aivojemme hermosolujen välisestä viestinnästä ja muodostavat molekulaarisen perustan korkeammille kognitiivisille toiminnoille kuten muistille ja oppimiselle. Glutamaattivälitteiset synapsit, jotka vastaavat pääasiallisesti aivojen eksitoivasta viestinnästä, kehittyvät asteittain ensimmäisten elinviikkojen aikana. Tämän kriittisen ajanjakson aikana ionotrooppisiin glutamaattireseptoreihin kuuluvat kainaattireseptorit (KAR) ilmentyvät hippokampuksessa voimakkaasti, ja niiden ajatellaan olevan tärkeitä hermosoluyhteyksien aktiivisuusriippuvaisessa kehityksessä. Kainaattireseptorien rakenteellinen vaihtelevuus on suurta riippuen siitä, miten viisi eri alayksikköä (GluK1-GluK5) yhdistyvät tetrameeriseksi reseptoriksi, sekä yksittäisten alayksiköiden lähetti-RNAn muokkauksesta (silmikointi ja editointi). Kainaattireseptorit muokkaavat ja säätelevät hermosolujen viestinvälitystä monin tavoin, mikä heijastuu reseptoreiden tarkasti säädeltyyn ja vaihtelevaan sijaintiin erilaisissa hermosoluissa. Vaikka tieto kainaattireseptoreiden monipuolisista tehtävistä synaptisen viestinvälityksen säätelyssä on viime aikoina lisääntynyt, niiden toimintaa hermoston kehityksen aikana ymmärretään huonosti. Tämän tutkimuksen tavoitteena oli selvittää kainaattireseptoreiden merkitystä glutamaattivälitteisen viestinnän kehityksessä rotan hippokampuksen CA1 alueella. Selvitimme kainaattireseptoreiden fysiologisia aktivaatiomekanismeja kehittyvissä CA3-CA1 synapseissa, niiden molekulaarista taustaa sekä vaikutuksia glutamaattivälitteisten synaptisten yhteyksien muodostumiseen. Esittelemme työssä täysin uudenlaisen, varhaiskehitykseen rajoittuvan mekanismin, jolla kainaattireseptorit estävät toonisesti glutamaatin vapautumista presynaptisista päätteistä. Tällä tavoin kainaattireseptorit osallistuvat varhaiskehitykselle tyypilliseen synapsien hiljentämiseen, jonka ajatellaan olevan merkittävä tekijä synaptisten yhteyksien hienosäädössä. Osoitamme, että toonisen KAR-aktivaation taustalla on korkea-affiininen reseptoripopulaatio, joka säätelee glutamaatin vapautumista G-proteiinivälitteisellä mekanismilla. Näytämme, että KAR-alayksikkö GluK1c estää glutamaatin vapautumista presynaptisesta päätteestä ja että sen ilmentyminen hippokampuksen pyramidisoluissa vastaa ajanjaksoa, jolloin reseptorit ovat toonisesti aktiivisia. Näiden tulosten valossa esitämme, että GluK1c alayksikkö toimii olennaisessa osassa toonisesti aktiivisessa kainaattireseptorissa ja että alayksikön ilmentymisen voimakas lasku kehityksen aikana aiheuttaa toonisen aktivaation katoamisen. Lisäksi näytämme, että aktiivisuus-riippuvaiset mekanismit, kuten pitkäaikaispotentiaation induktio, johtavat korkea-affiinisten reseptoreiden nopeaan häviämiseen ja kypsille synapseille ominaiseen luotettavaan viestinvälitykseen. Osoitamme lisäksi hippokampuksen leikeviljemissä, että GluK1 alayksikön sisältävät kainaattireseptorit säätelevät glutamaattivälitteisten synapsien määrää. Endogeenisen GluK1 aktivaation pitkäaikainen estäminen synaptogeneesin aikana johti synapsimäärän huomattavaan kasvuun, mikä heijastaa reseptoreiden ratkaisevaa merkitystä synapsien muodostumisessa/stablilisaatiossa. Tämä väitöskirja tuo merkittävää uutta tietoa kainaattireseptoreiden merkityksestä glutamaattivälitteisten synapsien muovautumisessa kehittyvässä hippokampuksessa sekä syventää tietämystämme hermosoluyhteyksien aktiivisuusriippuvaisesta kehityksestä. Näiden mekanismien läpikotainen tietämys on perusta myös kainaattireseptoreiden patofysiologisten roolien ymmärtämiselle sekä spesifisten lääkehoitojen kehittämiselle

Geenisaksilla hermoston sairauksien jäljille

English summar

The majority of type 2 diabetic patients in Finnish primary care are at very high risk of cardiovascular events : A cross-sectional chart review study (STONE HF)

Publisher Copyright: © 2021 The AuthorsAims: To characterize clinical profiles, prevalence of chronic kidney disease (CKD), and treatment patterns in type 2 diabetes (T2D) and heart failure (HF) patients in Finnish primary care. Methods: A total of 1385 patients (1196 with T2D, 50 with HF, and 139 with T2D and HF) in 60 Finnish primary care centers were recruited to this cross-sectional study. Data on demographic and clinical characteristics, laboratory measurements, and medications were collected retrospectively from medical records. T2D patients were classified according to their risk of cardiovascular (CV) events as very high-risk (62%) and other patients (38%). Results: Of the T2D patients, 10% (139/1335) had a diagnosis of HF and 42% (457/1090) had stage 3–5 CKD and/or albuminuria based on laboratory measurement. Of the HF patients, 74% (139/189) had T2D and 78% (114/146) had stage 3–5 CKD and/or albuminuria. Metformin was the most frequently used medication in both very high-risk patients (74%) and other patients (86%). SGLT2 inhibitors and/or GLP-1 analogues were used by 37% of very high-risk patients compared to 42% in other patients. Conclusions: The majority of T2D patients in Finnish primary care are at very high risk of cardiovascular events. However, the implementation of treatments with proven cardioprotective effects in very high-risk patients is currently suboptimal.Peer reviewe

Hemofilian hoito ja kustannukset Suomessa

Lähtökohdat Hemofilia on harvinainen verenvuototauti. Potilaat suositellaan hoidettavan verenvuototautien hoitoon erikoistuneissa keskuksissa. HemoHEOR-tutkimuksessa kartoitimme aikuisten potilaiden hoidon toteutumista ja kustannuksia Suomen yliopistosairaaloissa.Menetelmät Tiedot yliopistosairaaloissa hoidossa olleiden täysi-ikäisten A- ja B-hemofiliapotilaiden (n = 168) terveyspalvelu- ja lääkekäytöstä sekä lääkemääräyksistä kerättiin potilaskertomuksista. Hoidon suorat kustannukset arvioitiin lääkkeiden tukkumyyntihintojen ja terveydenhuollon yksikkökustannusten perusteella.Tulokset Vuosien 2012–16 aikana arviolta 72 % aikuisista A-hemofilia- ja 67 % B-hemofiliapotilaista oli hoidossa yliopistosairaaloissa. Verenvuotojen vuosittaisen määrän mediaani oli aineistossa pieni, eikä neljäsosalla hemofiliapotilaista ollut vuotoja tutkimusjakson aikana. Enemmän kuin 80 % potilaista sai hyytymistekijäkorvaushoitoa, joka muodosti noin 97 % hemofilian hoidon suorista vuosittaisista kokonaiskustannuksista.Päätelmät Hemofilian hoidon tulokset suomalaisissa yliopistosairaaloissa ovat kansainvälisesti verrattuna erinomaisia ja hoitomuodon potilaskohtainen valinta onnistunutta. Potilaiden ohjaamista keskitetyn hoidon piiriin on edelleen tehostettava.</p

The majority of type 2 diabetic patients in Finnish primary care are at very high risk of cardiovascular events: A cross-sectional chart review study (STONE HF).

AimsTo characterize clinical profiles, prevalence of chronic kidney disease (CKD), and treatment patterns in type 2 diabetes (T2D) and heart failure (HF) patients in Finnish primary care.MethodsA total of 1385 patients (1196 with T2D, 50 with HF, and 139 with T2D and HF) in 60 Finnish primary care centers were recruited to this cross-sectional study. Data on demographic and clinical characteristics, laboratory measurements, and medications were collected retrospectively from medical records. T2D patients were classified according to their risk of cardiovascular (CV) events as very high-risk (62%) and other patients (38%).ResultsOf the T2D patients, 10% (139/1335) had a diagnosis of HF and 42% (457/1090) had stage 3-5 CKD and/or albuminuria based on laboratory measurement. Of the HF patients, 74% (139/189) had T2D and 78% (114/146) had stage 3-5 CKD and/or albuminuria. Metformin was the most frequently used medication in both very high-risk patients (74%) and other patients (86%). SGLT2 inhibitors and/or GLP-1 analogues were used by 37% of very high-risk patients compared to 42% in other patients.ConclusionsThe majority of T2D patients in Finnish primary care are at very high risk of cardiovascular events. However, the implementation of treatments with proven cardioprotective effects in very high-risk patients is currently suboptimal.</p

Quo Vadis Architectura? 7. Mixing the Private and the Public in the City

In this book, experts from different fields discuss the changing boundaries between private and public city life, both from historical as well as contemporary perspectives. The publication is based on the 13th Quo Vadis Architectura? Nils Erik Wickberg Lectures, held at Aalto University in 2017. The seminar was organized by the chairs of History of Architecture, Housing and Urban and Regional Planning

Expression of GluK1c underlies the developmental switch in presynaptic kainate receptor function

Peer reviewe

Unraveling of Central Nervous System Disease Mechanisms Using CRISPR Genome Manipulation

The complex structure and highly variable gene expression profile of the brain makes it among the most challenging fields to study in both basic and translational biological research. Most of the brain diseases are multifactorial and despite the rapidly increasing genomic data, molecular pathways and causal links between genes and central nervous system (CNS) diseases are largely unknown. The advent of an easy and flexible CRISPR-Cas genome editing technology has rapidly revolutionized the field of functional genomics and opened unprecedented possibilities to dissect the mechanisms of CNS disease. CRISPR-Cas allows a plenitude of applications for both gene-focused and genome-wide approaches, ranging from original "gene scissors" making permanent modifications in the genome to the regulation of gene expression and epigenetics. CRISPR technology provides a unique opportunity to establish new cellular and animal models of CNS diseases and holds potential for breakthroughs in the CNS research and drug development.Peer reviewe

Kainate receptors in the developing neuronal networks

Kainate receptors (KARs) are highly expressed in the immature brain and have unique developmentally regulated functions that may be important in linking neuronal activity to morphogenesis during activitydependent fine-tuning of the synaptic connectivity. Altered expression of KARs in the developing neural network leads to changes in glutamatergic connectivity and network excitability, which may lead to longlasting changes in behaviorally relevant circuitries in the brain. Here, we summarize the current knowledge on physiological and morphogenic functions described for different types of KARs at immature neural circuitries, focusing on their roles in modulating synaptic transmission and plasticity as well as circuit maturation in the rodent hippocampus and amygdala. Finally, we discuss the emerging evidence suggesting that malfunction of KARs in the immature brain may contribute to the pathophysiology underlying developmentally originating neurological disorders.Peer reviewe

Quo Vadis Architectura? 8 - Nils Erik Wickberg lectures

The Department of Architecture at Aalto University has organized annual Nils Erik Wickberg lectures since 2005 to honour his legacy. Professor Wickberg was an architect, architectural historian, and multi-talented ideologist. This book comprises lectures from the 14th Symposium held in autumn 2018 on the theme of Quo Vadis Classicism? When considering the theme of the 2018 lectures, we tried to find a topic that touches on both the history of architecture and contemporary architectural design. In recent architecture, traces ofClassicism can once again be found. Classicism is usually associated with harmony, restraint, and adherence to the recognised principles of the form and style of ancient Greece or Rome. In recent student projects and competition entries by young architects, we can seesymmetrical facades, gable roofs, vertical windows, and other Classical features after a long period of Modernism. The Symposium Programme began with Professor Aino Niskanen’s introduction to the theme, and continued with Professor Vilhelm Helander’s presentation of C.L. Engel’s architecture in theEuropean context, after which Professor Simo Paavilainen spokeabout 1920s Nordic Classicism. Before the lunch break, we heard music from the Classical period, played by Tuija Hakkila on forte- piano and Mikael Helasvuo on flute. In the afternoon it was the turn of the young architects: Paul Thynell and Erkko Aarti, and finally, the keynote speaker, architect Johan Celsing from Sweden, gave an inspiring lecture entitled ´Plans, Metres. How the Work of Poets May Inform the Crafting of Buildings´. His poetry recitation made the event special. I hope that this publication stimulates new interpretations of Classical architecture and reminds us of the interesting lectures in October 2018 at Aalto Hall. Helsinki, November 24th 2020, Pirjo Sanaksenaho, Professor of Building Design, Head of Department of Architecture, Aalto University, School of Arts, Design and Architectur