Cell-type Specific Epigenomic and Transcriptomic Alterations in the Frontal Cortex of Individuals with Schizophrenia and the Impact of Antipsychotic Treatment

Core Concepts

Schizophrenia subjects exhibit thousands of neuronal and non-neuronal epigenetic differences at regions associated with schizophrenia risk, and antipsychotic treatment reverses some of these alterations while inducing additional epigenomic changes.

Abstract

The study conducted ChIP-seq and RNA-seq analyses on frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls. Key findings: Schizophrenia subjects showed thousands of differential enhancers, promoters, and differentially expressed genes in both neuronal (NeuN+) and non-neuronal (NeuN-) nuclei compared to controls. These alterations were enriched at genetic loci associated with schizophrenia risk. Analyzing the AF and AT cohorts separately revealed: Schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic/transcriptomic features that were reversed by antipsychotic treatment. Alterations that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia, such as changes in pathways related to p53 regulation. The effect of age on epigenomic landscapes was more pronounced in the frontal cortex of AT-schizophrenics compared to AF-schizophrenics and controls, suggesting antipsychotic treatment modulates age-related epigenomic changes. Overall, the study provides evidence of cell-type specific epigenetic and transcriptional alterations in schizophrenia, and highlights the impact of antipsychotic treatment and aging on the molecular landscape of the frontal cortex.

Stats

"Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3." "236 out of our 802 DEGs (p-value = 1.96 × 10-11) in NeuN+ nuclei, and 63 out of our 1043 DEGs (p-value = 4.18 × 10-6) in NeuN- nuclei were also identified in a previous single-cell dissection work." "The difference between AT-schizophrenia subjects and control pairs correlated either positively (WNK1) or negatively (SFRP2) with age."

Quotes

"Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3." "The difference between AT-schizophrenia subjects and control pairs correlated either positively (WNK1) or negatively (SFRP2) with age." "Hallucinations and delusions typically attenuate with aging, which is consistent with the lower PPR difference for EGR2 – a preclinical marker of psychosis-like behavior – that we observed in older subjects."

Key Insights Distilled From

Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia

by Zhu,B., Ains... at www.biorxiv.org 07-16-2021

https://www.biorxiv.org/content/10.1101/2021.07.14.452426v3

Deeper Inquiries

How do the epigenomic and transcriptomic alterations identified in this study compare to findings from other brain regions or cell types in schizophrenia?

In this study, the researchers focused on the frontal cortex samples from individuals with schizophrenia to analyze epigenomic and transcriptomic alterations. Comparing these findings to studies in other brain regions or cell types in schizophrenia, we can see both similarities and differences. Previous research has explored epigenetic and transcriptomic changes in various brain regions such as the prefrontal cortex, anterior cingulate cortex, and hippocampus, as well as in specific cell types like neurons and glial cells. One key similarity is the identification of alterations in genes and pathways related to synaptic plasticity, neurodevelopment, and neurotransmission. These common findings across different brain regions and cell types suggest a shared molecular signature of schizophrenia that involves dysregulation of these fundamental processes. Additionally, the involvement of specific genes like NRG1, GRM3, DRD3, and pathways related to glutamatergic neurotransmission and synaptic function have been consistently implicated in schizophrenia across different studies. However, there are also differences in the specific genes, pathways, and regulatory mechanisms identified in different brain regions and cell types. For example, the impact of age on gene expression and epigenetic regulation may vary between brain regions, leading to region-specific alterations. Additionally, the response to antipsychotic treatment and the compensatory epigenomic changes induced by these medications may differ in various cell types, influencing the therapeutic efficacy in a cell-specific manner. Overall, while there are commonalities in the epigenomic and transcriptomic alterations observed in schizophrenia across different brain regions and cell types, there are also unique features that reflect the complexity and heterogeneity of the disorder.

How do the epigenomic and transcriptomic alterations identified in this study compare to findings from other brain regions or cell types in schizophrenia?

The epigenomic and transcriptomic alterations identified in this study suggest that antipsychotic treatment induces compensatory changes in the frontal cortex of individuals with schizophrenia, potentially limiting the therapeutic efficacy of these medications. Several mechanisms may underlie these compensatory epigenomic changes: Neurotransmitter Receptor Regulation: Antipsychotic medications target neurotransmitter receptors such as dopamine and serotonin receptors. Prolonged exposure to these drugs can lead to alterations in the expression of these receptors, resulting in compensatory changes to maintain homeostasis in neurotransmission pathways. Neuroplasticity and Synaptic Function: Antipsychotics can impact neuroplasticity and synaptic function, leading to changes in gene expression and chromatin remodeling. Compensatory mechanisms may be activated to counteract the effects of antipsychotic drugs on synaptic plasticity and neuronal communication. Inflammatory Response: Antipsychotic medications can modulate the immune response and inflammatory pathways in the brain. Compensatory epigenomic changes may occur in response to alterations in immune signaling, affecting gene expression patterns related to inflammation and neuroprotection. Stress Response and Hormonal Regulation: Antipsychotic treatment can influence stress response pathways and hormonal regulation in the brain. Compensatory epigenomic changes may be triggered to adapt to these alterations, impacting gene expression profiles associated with stress resilience and hormonal balance. Overall, the compensatory epigenomic changes induced by antipsychotic treatment in individuals with schizophrenia reflect the complex interplay between drug effects, neural circuits, and molecular pathways in the brain. Understanding these mechanisms is crucial for optimizing treatment strategies and improving therapeutic outcomes in schizophrenia.

Could the age-related epigenomic changes observed in antipsychotic-treated schizophrenia subjects contribute to the cognitive decline often seen in this population, and are there opportunities for interventions to mitigate these effects?

The age-related epigenomic changes observed in antipsychotic-treated schizophrenia subjects may indeed contribute to the cognitive decline often seen in this population. As individuals with schizophrenia age, they may experience accelerated cognitive decline, which can be influenced by a combination of factors including disease progression, medication effects, and age-related changes in gene expression and chromatin regulation. The epigenomic changes associated with aging in antipsychotic-treated schizophrenia subjects may impact cognitive function through several mechanisms: Neuroplasticity and Synaptic Function: Age-related epigenomic changes can affect genes involved in neuroplasticity and synaptic function, leading to alterations in neuronal connectivity and cognitive processing. These changes may contribute to cognitive decline in individuals with schizophrenia. Inflammation and Oxidative Stress: Aging is associated with increased inflammation and oxidative stress in the brain, which can impact cognitive function. Epigenomic alterations related to these processes may exacerbate cognitive decline in antipsychotic-treated schizophrenia subjects. Neurotransmitter Signaling: Age-related changes in gene expression and chromatin regulation can influence neurotransmitter signaling pathways, affecting cognitive processes such as memory, attention, and executive function. Dysregulation of these pathways may contribute to cognitive decline in this population. Interventions to mitigate the effects of age-related epigenomic changes on cognitive decline in antipsychotic-treated schizophrenia subjects may include: Lifestyle Modifications: Healthy lifestyle choices such as regular exercise, balanced diet, and cognitive stimulation can help support cognitive function and mitigate the impact of age-related epigenomic changes. Pharmacological Interventions: Targeted pharmacological interventions that modulate epigenetic mechanisms or neuroprotective pathways may offer potential benefits in preserving cognitive function in aging individuals with schizophrenia. Psychosocial Support: Social engagement, cognitive training, and mental health support programs can provide cognitive stimulation and emotional well-being, which are important factors in maintaining cognitive health in this population. By addressing age-related epigenomic changes and their impact on cognitive decline in antipsychotic-treated schizophrenia subjects, tailored interventions can be developed to support cognitive function and overall well-being in aging individuals with schizophrenia.