Biology subjects

Tiihonen, J.

Publications and source records attributed to Tiihonen, J..

10 recordsLinked to original sources

bioRxiv2025

A schizophrenia-associated radial glia cell state perturbs early human brain development

Multidisciplinary evidence support a neurodevelopmental origin for schizophrenia, yet the mechanistic translation of known risk factors remains poorly understood. In this study, we leverage multi-lineage, forebrain-patterned organoids derived from monozygotic twins discordant for schizophrenia, integrating single-cell transcriptomic and epigenomic profiling to uncover disease-associated gene expression and chromatin accessibility topics. By constructing fate probability maps, we identify an accelerated developmental trajectory emerging from a distinct, schizophrenia-associated radial glia cell state, and reveal unique interactions among schizophrenia risk genes through unbiased multimodal analyses. Further, we confirm that schizophrenia-enriched states persist in differentiated lineages and disrupt synaptic programs, accompanied by molecular and cellular phenotypes mimicking observed disease pathology. Collectively, our findings delineate an early disruption in forebrain development, providing novel mechanistic insights into the origins of schizophrenia risk.

neuroscience↗

bioRxiv2024

Dopamine D2R and opioid MOR availability in autism spectrum disorder

Opioid and dopamine receptor systems are implicated in the pathoetiology of autism, but in vivo human brain imaging evidence for their role remains elusive. Here, we investigated regional type 2 dopamine and mu-opioid receptor (D2R and MOR, respectively) availabilities and regional interactions between the two neuromodulatory systems associated with autism spectrum disorder (ASD). In vivo positron emission tomography (PET) with radioligands [11C]raclopride (D2R) and [11C]carfentanil (MOR) was carried out in 16 adult males with high functioning ASD and 19 age and sex matched controls. Regional group differences in D2R and MOR receptor availabilities were tested with linear mixed models and associations between regional receptor availabilities were examined with correlations. There were no group differences in whole-brain voxel-wise analysis of DR2 but ROI analysis presented a lower overall mean D2R availability in striatum of the ASD versus control group. Post hoc regional analysis revealed reduced D2R availability in nucleus accumbens of the ASD group. The whole-brain voxel-wise analysis of MOR revealed precuneal up-regulation in the ASD group, but there was no overall group difference in the ROI analysis for MOR. MOR down-regulation was observed in the hippocampi of the ASD group in a post hoc analysis. Regional correlations between D2R and MOR availabilities were weaker in the ASD group versus control group in the amygdala and nucleus accumbens. These alterations may translate to disrupted modulation of social motivation and reward in ASD.

neuroscience↗

bioRxiv2023

Astrocytes regulate neuronal network burst frequency through NMDA receptors species- anddonor-specifically

BackgroundDevelopment of synaptic activity is a neuronal key characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known how human astrocytes influence neuronal activity. MethodsWe established human induced pluripotent stem cell (hiPSC)-derived neuron-astrocyte co-cultures and studied their functional development on microelectrode array (MEA). We used cell lines from 5 neurotypical control individuals and 3 pairs of monozygotic twins discordant for schizophrenia. A method combining Ngn2 overexpression and dual SMAD inhibition was used for neuronal differentiation. The neurons were co-cultured with hiPSC-derived astrocytes differentiated from 6-month-old astrospheres or rat astrocytes. ResultsWe found that the hiPSC-derived co-cultures develop complex network bursting activity similarly to neuronal co-cultures with rat astrocytes. However, the effect of NMDA receptors on neuronal network burst frequency (NBF) differed between co-cultures containing human or rat astrocytes. By using co-cultures derived from patients with schizophrenia and unaffected individuals, we found lowered NBF in the affected cells. We continued to demonstrate how astrocytes from an unaffected individual rescue the lowered NBF in the affected neurons by increasing NMDA receptor activity. ConclusionsOur results indicate that astrocytes participate in the regulation of neuronal NBF through a mechanism involving NMDA receptors. These findings shed light on the importance of using human and donor-specific astrocytes in disease modeling.

neuroscience↗

bioRxiv2023

Kynurenic acid promotes activity-dependent synaptic pruning in schizophrenia

Schizophrenia is a neurodevelopmental disorder characterized by an excessive loss of synapses. Recent data suggest that this is due to increased microglia-mediated synaptic pruning. Here, we utilize human induced pluripotent stem cell-derived models to show that kynurenic acid (KYNA), an endogenous NMDA-receptor antagonist observed to be increased in the brains of individuals with schizophrenia, reduces neuronal activity and promote microglial uptake of synapses. In a human brain organoid model, we confirm reduced microglia-mediated synaptic pruning upon inhibiting the endogenous KYNA production. To verify our experimental data in a clinical context, we integrate large-scale transcriptomic and genetic datasets and show that KYNA-producing kynurenine aminotransferases (KATs) enrich for genes governing synaptic activity and genetic risk variants for schizophrenia. Together, these results link genetic risk variants for schizophrenia to elevated production of KYNA and excessive activity-dependent synaptic pruning, while implicating pharmacological inhibition of KATs as a strategy to avoid synapse loss in schizophrenia.

neuroscience↗

bioRxiv2023

Oligodendrocyte precursor cells engulf synapses in a model of the developing human forebrain

Recent work in animal models suggests the role of oligodendrocyte precursor cells (OPCs) is not limited to oligodendrogenesis. Here, we report that OPCs derived from human induced pluripotent stem cells are capable of engulfing synaptosomes. We then develop a novel multi-lineage forebrain organoid in which OPCs alongside microglia display a spontaneous internalization of synaptic material in their phagolysosomes. Collectively, these findings suggest that OPCs contribute to synapse elimination in the developing human forebrain and provide a versatile platform for evaluating the interplay between microglia and OPCs in remodeling neuronal circuits in health and disease.

neuroscience↗

bioRxiv2023

Aberrant type 2 dopamine receptor availability in criminal psychopathy

BackgroundPsychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. MethodsHere we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n=11) and healthy matched controls (n=19) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. ResultsPsychopathic subjects had lowered D2R availability in caudate and putamen, and D2R striatal availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability amygdala and nucleus accumbens. ConclusionsWe conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for the aberrant MOR system is more limited.

neuroscience↗

bioRxiv2021

Mu-opioid receptor system modulates responses to vocal bonding and distress signals in humans

Laughter is a contagious prosocial signal that conveys bonding motivation; adult crying conversely communicates desire for social proximity by signalling distress. Endogenous mu-opioid receptors (MORs) modulate sociability in humans and non-human primates. In this combined PET-fMRI study (n=17) we tested whether central MOR tone is associated with regional brain responses to social signals of laughter and crying sounds. MOR availability was measured with positron emission tomography using high-affinity agonist radioligand [11C]carfentanil. Haemodynamic responses to social laughter and crying sounds were measured using functional magnetic resonance imaging (fMRI). Social laughter evoked activation in the auditory cortex, insula, cingulate cortex, amygdala, primary and secondary somatosensory cortex, primary and secondary motor cortex; crying sounds led to more restricted activation in auditory cortex and nearby areas. MOR availability was negatively correlated with the haemodynamic responses to social laughter in primary and secondary somatosensory cortex, primary and secondary motor cortex, posterior insula, posterior cingulate cortex, precuneus, cuneus, temporal gyri, and lingual gyrus. For crying-evoked activations, MOR availability was negatively correlated with medial and lateral prefrontal haemodynamic responses. Altogether our findings highlight the role of MOR system in modulating acute brain responses to both positive and negative social signals.

neuroscience↗

bioRxiv2021

Aberrant motor contagion of emotions in psychopathy and high-functioning autism

Psychopathy and autism are both associated with aberrant social interaction and communication, yet only psychopaths are markedly antisocial and violent. Here we compared the functional neural alterations underlying these two different phenotypes with distinct patterns of socioemotional difficulties. We studied 19 incarcerated male offenders with high psychopathic traits, 20 males with high-functioning autism and 19 age-matched healthy controls. All groups underwent functional magnetic resonance imaging while they viewed dynamic happy, angry and disgust facial expressions or listened to laughter and crying sounds. Psychopathy was associated with reduced somatomotor responses to almost all expressions, while subjects with autism demonstrated less marked and emotion-specific alterations in the somatomotor area. These data suggest that psychopathy and autism involve both common and distinct functional alterations in the brain networks involved in socioemotional processing.

neuroscience↗

bioRxiv2020

Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

Human astrocytes are multifunctional brain cells and may contribute to the pathophysiology of schizophrenia (SCZ). We differentiated astrocytes from induced pluripotent stem cells of monozygotic twins discordant for SCZ, and found sex-specific gene expression and signaling pathway alterations related particularly to inflammation and synaptic functions. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins, and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in demyelination, synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Altogether, our results show that astrocytes contribute to both familial risk and clinical manifestation of SCZ in a sex-specific manner.

neuroscience↗

bioRxiv2020

Molecular signaling pathways underlying schizophrenia

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell-derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data-driven causal molecular pathways involved. We used Ingenuity Pathway Analysis (IPA) to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. In contrast, no dopamine-specific genes were consistently involved. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA -related pathway, compared to those time periods when the same individual did not use the drug. This association was not attributable to general adherence to drug treatments. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA -related purine, oxidative stress, and glutamatergic signaling pathways are primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia - could be potential treatments before the full manifestation of illness involving dopaminergic abnormalities.

neuroscience↗