Brn-4 is Upregulated in the Deafferented Hippocampus and Promotes Neuronal Differentiation of Neural Progenitors In Vitro

Fimbria-fornix (FF), the septo-hippocampal pathway, was transected to model Alzheimer's disease (AD), which is characterized by loss of cholinergic afferent fibers in hippocampus. Various alternations may happen in the deafferented hippocampus. In this study, we determined the expression of Brn-4 in hippocampus after FF lesion. RTPCR and Western blot showed that mRNA transcription and protein of Brn-4 increased significantly and reached to the peak at day 14 after FF lesion. Hybridization and immunohistochemistry indicated that Brn-4 signals in hippocampus and dentate gyrus (DG) of the deafferented side were significantly stronger than the normal side. More Brn-4 positive cells were identified in the DG of deafferented hippocampus. In the pyramidal and granular cells, Brn-4 positive cells were all NeuN positive neurons, whereas in the neurogenic area, subgranular zone (SGZ), only a part of Brn-4 positive cells were NeuN positive, and these Brn-4/NeuN double positive neurons in SGZ and hilus of DG increased significantly after the trauma induced by FF lesion. In vitro Brn-4 antibody attenuated the role of extract from deafferented hippocampus in promoting differentiation of hippocampal progenitors into MAP-2 positive neurons. This study demonstrated that after FF lesion, Brn-4 in the deafferented hippocampus was upregulated and might play an important role in inducing local progenitors to differentiate into neurons, which may compensate for the loss of cholinergic afferent fibers or other dysfunctions. (C) 2008 Wiley-Liss, Inc.