Necl1 deficiency induces noradrenergic dysfunction and depressive-like states in rodents: A cross-species model validated by pharmacological intervention.

Abstract

BACKGROUND: Major depressive disorder (MDD), as a common mental disorder, has been one of the leading causes of disability worldwide for the past thirty years. It involves synaptic dysfunction, yet molecular mechanisms remain elusive, and more suitable animal models are needed for research. Necl1 (Nectin-like molecule 1), a adhesion molecule predominantly expressed within the nervous system, plays a key role in the regulation of synaptic formation and function. However, it is still unclear whether NECL1 is involved in the occurrence of MDD. RESULTS: Here we successfully generated constitutive Necl1 knockout (KO) models in both rats and mice, which recapitulated clinical phenotypes: rats exhibited depression-dominant behaviors (reduced sucrose preference; increased immobility in forced swim tests), while mice showed anxiety-dominant symptoms (prolonged novelty-suppressed feeding latency; decreased entries into open-field center zones). We showed that Necl1 deficiency in rats caused prefrontal-specific noradrenergic dysfunction characterized by norepinephrine (NE) depletion, dendritic spine loss, and adrenergic receptor α2A (Adra2a) upregulation, directly linking synaptic adhesion to catecholamine dysregulation. Adra2a antagonism (mirtazapine) rescued depressive phenotypes, and prefrontal cortex (PFC)-targeted Necl1 reconstitution not only rescued depressive phenotypes, but also normalized the expression Adra2a. Cross-species validation confirmed conserved noradrenergic vulnerability, with reboxetine ameliorating anxiety in mice. CONCLUSIONS: Our study establishes Necl1 as a synaptic-noradrenergic integrator that gates emotional processing via region-specific circuits. The Necl1 knockout rat serves as a stable genetic model of depression, while the knockout mouse presents a valuable model for studying anxiety-related mechanisms, together providing a cross-species platform for investigating emotional regulation.