Hippocampal mechanisms and neural circuitry of negative symptoms in schizophrenia

Negative symptoms represent a debilitating core of schizophrenia symptomatology that fail to respond to treatment with D2 antagonist antipsychotic drugs and may even be exacerbated by D2 antagonism. The neurobiological mechanisms underlying these symptoms are proposed to be related to limbic hippocampal hyperactivity, which is associated with the loss of parvalbumin-expressing GABAergic interneurons. This hippocampal hyperexcitability generates aberrant excitatory and dysrhythmic output to key limbic regions. Dysregulation of limbic hippocampal projections to the ventral striatum could impair reward processing, while disrupted connectivity with the prefrontal cortex and amygdala may underlie deficits in motivation, effort-based decision-making, and social behavior. We propose a two-dimensional clinical framework for negative symptoms to better understand their neurobiological mechanism, by segregating symptoms into diminished expressivity and amotivation domains. We also explore how biological sex serves as a critical factor of individual variability in symptom expression. For instance, males tend to have greater social withdrawal and avoidance, while females often show vulnerability to affect and mood disturbances. Understanding these circuit-level pathologies offers a mechanistic basis for the development of emerging treatments, such as GABAergic modulators, glutamatergic agents, and muscarinic agonists, which aim to restore normal hippocampal excitability. A dimensional, biomarker-informed approach could advance the development of personalized therapeutic strategies and ultimately improve functional outcomes for individuals living with schizophrenia.