Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20–22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic- but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABAB receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABAB signaling. Consistently, we find an increased expression of the GABAB1 receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.

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Aging, the greatest risk factor for Alzheimer's disease (AD), may lead to the accumulation of somatic mutations in neurons. We investigated whether somatic mutations, specifically in longer genes, are implicated in AD etiology. First, we modeled the theoretical likelihood of genes being affected by aging‐induced somatic mutations, dependent on their length. We then tested this model and found that long genes are indeed more affected by somatic mutations and that their expression is more frequently reduced in AD brains. Furthermore, using gene‐set enrichment analysis, we investigated the potential consequences of such long gene disruption. We found that long genes are involved in synaptic adhesion and other synaptic pathways that are predicted to be inhibited in the brains of AD patients. Taken together, our findings indicate that long gene–dependent synaptic impairment may contribute to AD pathogenesis.

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Late-onset Alzheimer’s disease (AD) has a significant genetic and immunological component, but the molecular mechanisms through which genetic and immunity-related risk factors and their interplay contribute to AD pathogenesis are unclear. Therefore, we screened for genetic sharing between AD and the blood levels of a set of cytokines and growth factors to elucidate how the polygenic architecture of AD affects immune marker profiles. For this, we retrieved summary statistics from Finnish genome-wide association studies of AD and 41 immune marker blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 15 cytokines and growth factors, we identified genetic sharing with AD. We also found positive and negative genetic concordances—implying that genetic risk factors for AD are associated with higher and lower blood levels—for several immune markers and were able to relate some of these results to the literature. Our results imply that genetic risk factors for AD also affect specific immune marker levels, which may be leveraged to develop novel treatment strategies for AD.

Background Aging is associated with the accumulation of somatic mutations in post‐mitotic neurons. While this idea is not new, recent advances in single‐cell sequencing techniques have now made it possible to not only unequivocally prove that these mutations occur but also to estimate their occurrence rates. Here, we aimed to investigate whether somatic mutations are associated with Alzheimer’s disease (AD) and gain insight into the potential pathophysiological consequences of such mutations in the brain. Method Starting from the average annual somatic variation rate of healthy neurons, we modeled the likelihood of a gene being affected by somatic mutations over time, based on the transcribed length of that gene. Subsequently, we investigated the gene length distribution of genes that are affected by somatic mutations in AD brains and we analyzed differential mRNA expression data from eight AD brain areas, including pathway analysis. Result Our model predicted that CNTNAP2, the largest gene in the human genome, has a 50% chance of having acquired at least one somatic mutation by the age of 65, which is in sharp contrast with average‐sized genes, in which there is only 1% chance of somatic mutations at 65. We also found that genes affected by somatic mutations are (much) longer than average and that larger genes are more likely to be reduced in their expression levels in AD‐vulnerable brain regions. Lastly, we found that these larger genes are predominantly expressed in neurons and are involved in synaptogenesis and synaptic adhesion, pathways that are predicted to be inhibited in AD based on the transcriptomic data. Conclusion Our findings implicate somatic mutations in large genes as potential contributors to AD pathology through their effect on synaptic function.