Polyamine stress response in schizophrenia: A translational framework beyond monoamine-centered models

Area of Science:

• Neuroscience
• Psychiatry
• Systems Biology

Background:

• Current schizophrenia treatments primarily target dopamine, leaving unmet needs in negative symptoms, cognition, and functioning.
• The Polyamine Stress Response (PSR) is proposed as a conserved, systems-level program relevant to brain disorders.

Purpose of the Study:

• To introduce the Polyamine Stress Response (PSR) as a novel framework for understanding schizophrenia.
• To identify actionable targets within the PSR for therapeutic intervention.

Main Methods:

• Literature review and synthesis of evidence from human and animal studies.
• Analysis of the arginine-nitric oxide-agmatine-polyamine pathway.
• Exploration of insights from plant biology and infection-mimicking psychoses.

Main Results:

• The PSR involves stress-driven resetting of polyamine pools, impacting oxidative load, glial function, membrane dynamics, and circuit stability.
• Agmatinase is identified as a potential regulatory node in agmatine metabolism.
• Upstream polyamine synthesis steps are potentially targetable with inhibitors.

Conclusions:

• The PSR offers a new mechanistic and translational context for schizophrenia research.
• Modulating polyamine flux presents a promising therapeutic strategy, with potential for biomarker-stratified approaches.