Disrupted-in-schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization

Area of Science:

• Neuroscience
• Molecular Psychiatry
• Computational Neuroscience

Background:

• Aberrant protein aggregation and proteostasis disruption are implicated in chronic mental illnesses (CMI).
• Neuronal activity alterations underlying CMI remain poorly understood.
• Disrupted-in-Schizophrenia 1 (DISC1) gene overexpression models sporadic CMI, leading to protein aggregation and behavioral deficits.

Purpose of the Study:

• To investigate hippocampal neural coding and network synchrony alterations in a rat model of CMI.
• To link DISC1 protein pathology to specific neuronal and network dysfunctions.
• To understand the mechanisms of CMI at the neural circuit level.

Main Methods:

• In vivo electrophysiological recordings (local field potential and single-unit activity) in the hippocampal CA1 region of tgDISC1 rats and controls.
• Recordings during exploration of familiar/novel environments and during sleep to assess unconstrained behavior.
• Analysis of place cell properties, firing rate speed-modulation, and oscillatory activity (theta and gamma phase locking).

Main Results:

• tgDISC1 rats exhibited smaller place fields and reduced speed-modulation of place cell firing, indicating impaired spatial coding.
• Pyramidal neurons in tgDISC1 rats showed increased theta phase locking during novelty and reduced population-level theta phase variability, impairing network synchronization.
• tgDISC1 neurons lacked novelty-induced shifts in preferred theta and gamma firing phases, demonstrating deficits in coding novel environments.

Conclusions:

• DISC1 protein pathology is directly linked to abnormal hippocampal neural coding, including spatial and temporal aspects.
• Network synchrony deficits, particularly during novelty, contribute to the pathophysiology of CMI.
• This study provides a comprehensive understanding of how DISC1 dysfunction impacts neural mechanisms underlying CMI.