Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia

Abstract

Schizophrenia (SZ) is a devastating psychiatric disorder affecting about 1% of the world’s population. Social-cognitive impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social-cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the whole-brain level, an abnormal activation of social brain regions and interregional dysconnectivity within social-cognitive brain networks have been identified as major contributors to these symptoms. At the cellular and subcellular levels, an interplay between oxidative stress, neuroinflammation and N-methyl-D-aspartate receptor hypofunction is thought to underly SZ pathology. However, it is not clear how these molecular processes are linked with interregional dysconnectivity in the genesis of social-cognitive symptoms. Here, we aim to bridge the gap between macroscale (connectivity analyses) and microscale (molecular and cellular mechanistic) knowledge by proposing impaired myelination and the disinhibition of local microcircuits as possible causative biological pathways leading to dysconnectivity and abnormal activity of the social brain. Furthermore, we recommend electroencephalography as a promising translational technique that can foster pre-clinical drug development and discuss attractive drug targets for the treatment of social-cognitive symptoms in SZ.

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model

“…Hence, it is possible that the lack of effect of aripiprazole was either because the dose tested was too strong or because it was not able to produce an effect on the root cause of social dysfunction. In fact, aripiprazole was also unable to recover the abnormalities found in evoked and spontaneous gamma oscillations in the model, two EEG parameters measuring aspects of the neuronal excitation/inhibition imbalance that underlies social dysfunction in SZ [8,9,14,18,19]. Thus, this suggests that aripiprazole's inefficacy towards social impairment in our study and its very limited effects against social deficits in SZ patients might be associated with (and potentially a consequence of) its inefficacy towards the aforementioned electrophysiological impairments that contribute to these symptoms.…”

“…Importantly, these electrophysiological dysfunctions have been associated with all the symptoms of SZ and may thereby provide valuable translational information regarding the therapeutic potential of investigational drugs [15][16][17][18]. Used in combination with traditional behavioral methods, these biomarkers could foster the preclinical development of new medicines for SZ and allow further characterization of already commercialized antipsychotics to better understand their effects (or absence of effect), thus providing valuable insights for new drug development aimed towards SZ [19].…”

“…Regarding behavioral manifestations specifically, NMDAr hypofunction is thought to produce further dysfunctions within mesolimbic and mesocortical dopaminergic pathways, contributing to positive symptoms (e.g., psychosis and agitation), cognitive impairment and negative symptoms, such as social withdrawal, in SZ patients and animal models [25,26]. Moreover, NMDAr hypofunction could directly contribute to social symptoms by provoking an imbalance between excitatory and inhibitory inputs, resulting in glutamate spillover from synapses and dysconnectivity within and between cortical and subcortical regions regulating social behavior [19]. In animal models based on pharmacological antagonism of NMDAr, the symptoms can be studied using various readouts such as social interaction deficits or hyperlocomotion, the latter being commonly used as a translational index of psychotic-like behavior.…”

Potential Schizophrenia Disease-Related Genes Prediction Using Metagraph Representations Based on a Protein-Protein Interaction Keyword Network: Framework Development and Validation

“…In genes with abnormal methylation, DNA methylation at CpG sites can regulate gene expression during disease processes [ 37 ]. Moreover, methylation can control the onset and progression of the neurodegeneration associated with different cell signaling pathways and dynamically regulate differentiated neurons.…”