Abstracts Day 1
Neuroinflammation and the kynurenine pathway in psychiatric disorders
Dr. Sophie Erhardt (KI/FyFa)
Emerging evidence suggests that inflammation has a key role in psychiatric disorders. The kynurenine pathway (KP) is involved in neuroinflammation and regulates glutamate neurotransmission by its metabolites quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, and kynurenic acid (KYNA), an NMDA receptor antagonist. Increased brain KYNA has been found in patients with schizophrenia whereas increased QUIN has been found in depressed patients with suicidal behaviour. Mechanisms controlling the activity of the KP may originate from genetic variations. Thus, the protein sorting nexin 7 (SNX7) initiates a caspase-8-driven activation of IL-1β that induces an enzyme in the KP. A genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of KYNA and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Moreover, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia. Elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of these disorders. In suicidal patients, we have identified the enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) as a contributor for the increased QUIN formation. Thus, the minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN.
Molecular imaging studies in schizophrenia
Dr. Simon Cervenka (KI/CNS)
The talk will give a brief overview of ongoing molecular imaging studies in schizophrenia at KI. Building on early work on striatal dopamine function at the KI PET centre, we are now examining dopamine D2-receptors in extrastriatal regions in drug naïve first-episode patients with psychosis. Furthermore, D1-receptors as a correlate of psychosis proneness in healthy individuals is explored using a combination of experimental behavioural tests and questionnaires. Another line of research aims to target the hypothesis of an immune system involvement in schizophrenia. Using radioligands for the 18-kD translocator protein (TSPO), it is possible to quantify glial cell activity in the brain. We recently applied this methodology in another group of first-episode patients, showing lower levels of TSPO binding. Ongoing work aims to elucidate the relationship between central TSPO levels and markers for peripheral and central immune activation, including applying a recently developed method to assess TSPO in peripheral blood cells. For both lines of research, we are also working on projects where PET is combined with both structural and functional imaging modalities.
Pro-inflammatory Cytokine Inhibitors for the Treatment of Neurodegenerative Disorders
Dr. Nigel Greig (NIH/NIA)
Clinical and preclinical studies reveal that basal inflammatory status increases as a function of normal aging, and development of a mild pro-inflammatory state closely associates with major degenerative diseases in the elderly. In line with this, levels of brain pro-inflammatory cytokines become elevated with age in rodents and humans, and several regulatory molecules and anti-inflammatory cytokines decline. Microglia, as a source of these pro- and anti-inflammatory molecules, are thereby implicated as the major culprit of this neuroinflammation. Rectifying the overproduction of pro-inflammatory cytokines by microglia may mitigate a broad number of neurodegenerative disorders prevalent in the elderly. Engaging an appropriate drug target to effectively achieve this has proved difficult, and accounts for the numerous failures of clinical trials of anti-inflammatory agents in neurodegenerative disorders. TNF-alpha, a key pro-inflammatory cytokine, is generated by microglial during their activated M1 state. If not appropriately time-dependently reduced by microglial transition to a M2 phase, excessive TNF-alpha synthesis initiates a self-propagating cycle of unchecked inflammation. Pharmacologically inhibiting this cycle may benefit disorders with a neuroinflammatory component. Our generation of TNF-alpha synthesis inhibitors is providing pharmacological probes to understand the role of TNF-alpha in disease processes as well as drug candidates to treat them.
Beyond inflammation: novel mechanisms driving pain in arthritis
Dr. Camilla Svensson (KI/FyFa)
Joint pain in rheumatoid arthritis (RA) often precedes joint inflammation and may persist even after successful anti-inflammatory treatment. We are exploring both peripheral and central mechanisms that can explain how joint pain is induced and maintained in RA and are focusing on the role of HMGB1, autoantibodies, antibody receptors, osteoclasts and glia cells.
Cognitive Neuroscience of Body Self-Perception
Dr. Henrik Ehrsson (KI/Neuro)
Ask any child if his hands belong to him and the answer will be “Of course!” But how does the brain actually identify its own body? A key idea is that parts of the body are distinguished from the external world by the patterns they produce of correlated information from different sensory modalities (vision, touch and muscle sense). These correlations are hypothesized to be detected by neuronal populations that integrate multisensory information from the space near the body. Dr. Ehrsson and his team have used a combination of functional magnetic resonance imaging and human behavioral experiments to present experimental evidence in support of these predictions. To change the feeling of body ownership, perceptual illusions were used where healthy individuals experienced that a rubber hand was their own, that a mannequin was their body (“body-swap illusion”), or, that they are outside their physical body and looking at it from the perspective of another individual (“out-of-body illusion”). By clarifying how the normal brain produces a sense of ownership of one’s body, we can learn to project ownership onto artificial bodies and simulated virtual ones; and even make two people have the experience of swapping bodies with one another. This could have ground-breaking applications in the fields of virtual reality and neuro-prosthetics.
Molecular and electrophysiological comparison of striatal and cortical Pvalb interneurons
Ms. Carolina Bengtsson Gonzales, KI-NIH Student (MBB/NICHD)
In cortex and striatum Parvalbumin (Pvalb+) interneurons (IN) display an unique high frequency firing pattern and direct somatic targeting, allowing them to exhibit a very strong and immediate inhibition of the targeting cell, and ultimately strongly control the circuit output. Having the same developmental origin, marker expression and circuit function, one would assume that the striatal Pvalb+ cells share similar gene expression profiles to their cortical counterparts.
Using singe cell RNA sequencing we were able to acquire single cell transcriptomic data from the S1 cortex, CA1 hippocampus and dorsal striatum. Showing striatal Pvalb+ INs unlike other subtypes are molecularly distinct to their hippocampal and cortical counterparts. Although grossly similar and clearly fast spiking, we also show that there are significant differences between the electrophysiological intrinsic properties of cortical and striatal Pvalb-cre labeled interneurons.
There is a stark contrast in the depth of knowledge with regards to basic micro circuitry in the striatum as compared to the cortex or hippocampus. However, our striatal single cell sequencing data suggests that the Pvalb+ IN are clustered within a larger population expressing Parathyroid hormone-like hormone (Pthlh+), with varying levels of Pvalb expression. Using patchseq we show that there is no differences in electrophysiological properties between the Pvalb-low and Pvalb-high subpopulations. Causing us to re-evaluate the role of gene expression in the function of a cell type.