A new method for modulating the activity of parvalbumin-positive neurons and cerebellar Purkinje cells in vivo

Neurons can be divided into various classes according to their location, morphology, neurochemical identity and electrical properties. They form complex interconnected networks with precise roles for each cell type. GABAergic neurons expressing the calcium-binding protein parvalbumin (Pv) are mainly interneurons, which serve a coordinating function. Pv-cells modulate the activity of principal cells with high temporal precision. Abnormalities of Pv-interneuron activity in cortical areas have been linked to neuropsychiatric illnesses such as schizophrenia. Cerebellar Purkinje cells are known to be central to motor learning. They are the sole output from the layered cerebellar cortex to deep cerebellar nuclei. There are still many open questions about the precise role of Pv-neurons and Purkinje cells, many of which could be answered if one could achieve rapid, reversible cell-type specific modulation of the activity of these neurons and observe the subsequent changes at the whole-animal level. The aim of these studies was to develop a novel method for the modulation of Pv-neurons and Purkinje cells in vivo and to use this method to investigate the significance of inhibition in these neuronal types with a variety of behavioral experiments in addition to tissue autoradiography, electrophysiology and immunohistochemistry. The GABA(A) receptor γ2 subunit was ablated from Pv-neurons and Purkinje cells in four separate mouse lines. Pv-Δγ2 mice had wide-ranging behavioral alterations and increased GABA-insensitive binding indicative of an altered GABA(A) receptor composition, particularly in midbrain areas. PC-Δγ2 mice experienced little or no motor impairment despite the lack of inhibition in Purkinje cells. In Pv-Δγ2-partial rescue mice, a reversal of motor and cognitive deficits was observed in addition to restoration of the wild-type γ2F77 subunit to the reticular nucleus of thalamus and the cerebellar molecular layer. In PC-Δγ2-swap mice, zolpidem sensitivity was restored to Purkinje cells and the administration of systemic zolpidem evoked a transient motor impairment. On the basis of these results, it is concluded that this new method of cell-type specific modulation is a feasible way to modulate the activity of selected neuronal types. The importance of Purkinje cells to motor control supports previous studies, and the crucial involvement of Pv-neurons in a range of behavioral modalities is confirmed.Hermosolut jaotellaan useisiin alatyyppeihin sijainnin, muodon sekä neurokemiallisten ja sähköisten ominaisuuksien perusteella. Ne muodostavat monimutkaisia toisiinsa kytkeytyneitä verkostoja, joissa jokaisella solutyypillä on oma tehtävänsä. Gamma-aminovoihappoa (GABA) sisältävät hermosolut, jotka ilmentävät kalsiumia sitovaa parvalbumiiniproteiinia (Pv) ovat lähinnä välihermosoluja, ja niillä on keskushermostossa tärkeä koordinoiva tehtävä. Pv-solut säätelevät tarkasti päähermosolujen, kuten pyramidisolujen aktiivisuutta. Poikkeavuudet Pv-välineuronien toiminnassa isoaivokuoren alueella on yhdistetty neuropsykiatrisiin sairauksiin, kuten skitsofreniaan. Pikkuaivojen Purkinjen solujen tiedetään olevan keskeisiä motorisen oppimisen kannalta. Ne vievät informaatiota pikkuaivojen kerroksittaiselta kuorialueelta pikkuaivojen syviin tumakkeisiin. Pv-solujen ja Purkinjen solujen toiminnassa on vielä paljon avoimia kysymyksiä, joihin voitaisiin vastata, jos olisi olemassa keino säädellä näiden hermosolujen aktiivisuutta nopeasti, palautuvasti ja solutyyppivalikoivasti, ja tarkastella mahdollisia muutoksia koe-eläinten käyttäytymisessä. Näiden tutkimusten tavoitteena oli kehittää uusi menetelmä Pv-hermosolujen ja Purkinjen solujen säätelyyn elävässä eläimessä, ja käyttää tätä menetelmää neuronaalisen inhibition merkityksen tutkimiseen näissä soluissa. Tutkimuksissa hyödynnettiin käyttäytymiskokeita, kudosautoradiografiaa, sähköfysiologiaa ja immunohistokemiallisia tekniikoita. GABA(A)-reseptorin γ2-alayksikkö poistettiin Pv-soluista ja Purkinjen soluista neljässä eri hiirikannassa. Pv-Δγ2-hiirillä havaittiin laaja-alaisia käyttäytymismuutoksia ja muutoksia GABA(A)-reseptorin alayksikkökoostumuksessa erityisesti keskiaivojen alueella. PC-Δγ2-hiirillä havaittiin vain vähän liikehäiriöitä, vaikka niiden Purkinjen soluista puuttui neuronaalista inhibitiota. Pv-Δγ2-partial rescue mice-hiirillä havaittiin lievää liike- ja tiedonkäsittelytoimintojen palautumista Pv-Δγ2-hiiriin verrattuna. PC-Δγ2-swap-hiirille saatiin palautettua osittainen herkkyys unilääke tsolpideemille, joka aiheutti niille väliaikaisia liikehäiriöitä. Näiden tulosten perusteella esitetään johtopäätös, että tämä Pv-hermosolujen ja Purkinjen solujen uusi säätelymenetelmä on käyttökelpoinen tapa muunnella valikoitujen hermosolutyyppien aktiivisuutta

Ro 15-4513 Antagonizes Alcohol-Induced Sedation in Mice Through aß¿2-type GABA(A) Receptors

Peer reviewedPublisher PD

Anti-doping knowledge and educational needs of Finnish pharmacists

Publisher Copyright: © 2021Objectives: Pharmacists’ role in health care has evolved towards a more collaborative practice to combat current public health challenges and to support rational use of medicines. Previous literature also demonstrates pharmacists’ emerging role in sports and exercise medicine, including anti-doping and health counselling of athletes. The aim of this study was to assess: 1) What is the pharmacists’ self-assessed knowledge about doping and anti-doping activities? 2) How does the pharmacists’ and pharmacy characteristics effect on the self-assessed knowledge about doping and anti-doping activities? 3) What educational needs do the pharmacists report about doping and anti-doping activities? Material and Methods: A cross-sectional online survey was conducted among Finnish pharmacists in 2019. A convenience sampling method was used to reach the target group. The survey consisted of 26 questions considering pharmacists’ perceptions about doping, knowledge, and need for education about the pharmacology of doping agents, anti-doping counselling, and information sources. Descriptive statistics and cross-tabulation with Pearson's χ2 and the Kruskal-Wallis tests were used to analyse the data. Results: A total of 246 pharmacy professionals completed a national online survey targeted at pharmacists in Finland. The average age of the respondents was 43 years (SD = 10), where 94% were females and 6% males. Pharmacists reported their self-assessed knowledge on anti-doping counselling to be poor or rather poor. Their highest needs for education were related to nutritional supplements’ doping risks, substances listed as doping agents, their mechanisms of action and purpose of use, and the adverse effects of doping agents and interactions with other medicines. More information was also needed about prohibited substances and methods in sports and doping in recreational sports. Conclusion: Pharmacists were willing to participate in anti-doping activities, including counselling athletes. However, many pharmacists perceived their knowledge as insufficient and reported educational needs that could be considered in undergraduate and continuing education of pharmacists. Universities, anti-doping organisations, and other related actors in the pharmacy and anti-doping field have an important role in providing more educational opportunities to pharmacists.Peer reviewe

Lääkeneuvonnan tukityökalujen kehittäminen antidopingneuvontaan apteekeissa - kyselytutkimus farmasian ammattilaisille

English summary.Peer reviewe

Does ethanol act preferentially via selected brain GABAA receptor subtypes? the current evidence is ambiguous

In rodent models, γ-aminobutyric acid A (GABAA) receptors with the α6 and δ subunits, expressed in the cerebellar and cochlear nucleus granule cells, have been linked to ethanol sensitivity and voluntary ethanol drinking. Here, we review the findings. When considering both in vivo contributions and data on cloned receptors, the evidence for direct participation of the α6-containing receptors to increased ethanol sensitivity is poor. The α6 subunit-knockout mouse lines do not have any changed sensitivity to ethanol, although these mice do display increased benzodiazepine sensitivity. However, in general the compensations occurring in knockout mice (regardless of which particular gene is knocked out) tend to fog interpretations of drug actions at the systems level. For example, the α6 knockout mice have increased TASK-1 channel expression in their cerebellar granule cells, which could influence sensitivity to ethanol in the opposite direction to that obtained with the α6 knockouts. Indeed, TASK-1 knockout mice are more impaired than wild types in motor skills when given ethanol; this might explain why GABAA receptor α6 knockout mice have unchanged ethanol sensitivities. As an alternative to studying knockout mice, we examined the claimed δ subunit-dependent/γ2 subunit-independent ethanol/[3H]Ro 15-4513 binding sites on GABAA receptors. We looked at [3H]Ro 15-4513 binding in HEK 293 cell membrane homogenates containing rat recombinant α6/4β3δ receptors and in mouse brain sections. Specific high-affinity [3H]Ro 15-4513 binding could not be detected under any conditions to the recombinant receptors or to the cerebellar sections of γ2(F77I) knockin mice, nor was this binding to brain sections of wild-type C57BL/6 inhibited by 1–100 mM ethanol. Since ethanol may act on many receptor and channel protein targets in neuronal membranes, we consider the α6 (and α4) subunit-containing GABAA receptors unlikely to be directly responsible for any major part of ethanol's actions. Therefore, we finish the review by discussing more generally alcohol and GABAA receptors and by suggesting potential future directions for this research.This study and review was supported by the Finnish Foundation for Alcohol Studies, the Academy of Finland and the Sigrid Juselius Foundation.Peer reviewe

Removal of GABA(A) Receptor gamma 2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations

Peer reviewe

Type 2 diabetes and treatment intensification in primary care in Finland

AimTo identify how the electronic health record (EHR) systems and national registers can be used for research purposes. We focused on how the primary care physicians adhere to clinical guidelines.MethodsStudy population included incident type 2 diabetes patients from four selected regions. Data were collected in two phases. At the first phase study cohort was identified using the prescription registers of the Social Insurance Institution (SII) and EHR systems used within the study regions. At second phase, data were collected from SII's registers, local EHR systems, the hospital discharge and the primary care registers of National Institute for Health and Welfare.ResultsMetformin was the most common choice as first drug. Among all study patients, 8375 (76.0%) started metformin monotherapy or combinations. The treatment was intensified at variable levels of HbA1c depending on the area. DPP4-inhibitors were by far the most common agent for treatment intensification. Sulphonylureas were used less often than basal insulin as the second-line agent. The use of DPP4-inhibitors increased between years 2009-2010, when first DPP4-inhibitor received reimbursement and this class became dominant drug for treatment intensification increasingly thereafter.ConclusionsThe EHR systems and national registers can be used for research purposes in Finland. The realization of diabetes treatment national guidelines are followed in primary care to a large extent. However, the subsequent intensification of therapy was delayed and occurred at elevated Hba1c levels.Peer reviewe

Genomilääketieteen sovelluksia sairauksien hoidossa

Teema : Genomitieto. English summar