Lipocalin-2 is involved in emotional behaviors and cognitive function

Lipocalin-2 is involved in emotional behaviors and cognitive functionLipocalin-2 (LCN2), an iron-related protein well described to participate in the innate immune response, has been shown to modulate spine morphology and to regulate neuronal excitability. In accordance, LCN2-null mice are reported to have stress-induced anxiety. Here we show that, under standard housing conditions, LCN2-null mice display anxious and depressive-like behaviors, as well as cognitive impairment in spatial learning tasks. These behavioral alterations were associated with a hyperactivation of the hypothalamic-pituitary-adrenal axis and with an altered brain cytoarchitecture in the hippocampus. More specifically, we found that the granular and pyramidal neurons of the ventral hippocampus, a region described to be associated with emotion, were hypertrophic, while neurons from the dorsal hippocampus, a region implicated in memory and cognition, were atrophic. In addition, LCN2-null mice presented synaptic impairment in hippocampal long-term potentiation. Whether the LCN2 effects are mediated through modulation of the level of corticosteroids or through a novel mechanism, the present observations bring further into light this immune-related protein as a player in the fine-tuning of behavior and of synaptic activity.We are grateful to Professor Shizuo Akira and Professor Cevayir Coban for the LCN2-null mice in the BALB/c background and to Professor Trude Flo for the LCN2-null mice in C57BL/6J background. Ana C. Ferreira, Sandro D. Mesquita, and Ashley Novais are recipients of Ph.D. and Fernanda Marques and Vitor Pinto are recipients of postdoctoral fellowships from Fundacao para a Ciencia e Tecnologia (Portugal)