NMDA receptor-dependent structural plasticity links early life stress to persistent aggression.

Early life stress (ELS) is a major risk factor for reactive and pathological aggression that can persist long after the original stress exposure. Across species, ELS produces enduring alterations in the neural circuits that regulate social behavior and aggression, yet the molecular, structural, and circuit mechanisms that stabilize these changes remain poorly defined. Emerging evidence implicates N-methyl-D-aspartate receptor (NMDAR)-dependent structural plasticity in aggression circuits as a mechanism linking early adversity to persistent aggressive behavior. In this review, we present a hypothesis-driven narrative that synthesizes clinical, postmortem, imaging, and preclinical evidence to define a testable framework for future research. We focus on how ELS may recruit NMDAR signaling to reshape excitatory connectivity within aggression circuits, with particular emphasis on the posterior ventral medial amygdala to ventrolateral ventromedial hypothalamus pathway. Within this pathway, preclinical studies suggest that ELS increases dendritic spine density, promotes excitatory shaft synaptogenesis, and biases synaptic input toward proximal dendritic locations predicted to exert stronger effects on neuronal firing. We propose that this location-specific remodeling may increase circuit excitability, thereby lowering the threshold for aggressive responding. We further examine the translational potential of targeting NMDAR-dependent plasticity, focusing on the clinically available antagonists ketamine and memantine. By integrating molecular, structural, circuit-level, and clinical perspectives, we propose that NMDAR-dependent control of synapse formation and location represents a plausible mechanism through which ELS persistently biases neural circuits that regulate aggression. Targeting these processes may provide new strategies for reducing pathological aggression following ELS.