Targeting of locus ceruleus noradrenergic neurons expressing human interleukin-2 receptor α-subunit in transgenic mice by a recombinant immunotoxin anti-Tac(Fv)-PE38: A study for exploring noradrenergic influence upon anxiety-like and depression-like behaviors

The noradrenergic (NA) neurons in the locus ceruleus (LC) were ablated with a high degree of selectivity by immunotoxin-mediated neuronal targeting. Transgenic mice were used in which the human interleukin-2 receptor-α subunit (hIL-2Rα; Tac) is expressed under the promoter of dopamine β-hydroxylase. The recombinant immunotoxin, which is composed of the Fv fragment of an anti-hIL-2Rα monoclonal antibody fused to atruncated form of Pseudomonas exotoxin [anti-Tac(Fv)-PE38], was injected bilaterally into the LC of the mouse. As a result, the LC-NA neurons disappeared almost completely, and tissue noradrenaline was depleted in brain regions that receive NA inputs from the LC. The decrement of tissue noradrenaline content was more profound compared with that in mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a neurotoxin capable of ablating axons originating from the LC-NA neurons. Mice treated with eitherthe immunotoxin or DSP-4 presented increased anxiety-like behaviors; in contrast, only the immunotoxin-treated mice, and not the DSP-4-treated mice, showed increased depression-like behavior. The immunotoxin-mediated neuronal targeting may provide a means for further unraveling the links between the LC and pathological manifestations of neurological disorders.