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

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

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

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.