Mathis C, Moreau P-H, Zerbinatti C, Goutagny R, Cosquer B, Geiger K, Kelche C, Cassel J-C (2012) Combined loss of entorhinal and basal forebrain cholinergic hippocampal inputs deeply impairs spatial navigation memory in C57BL/6J and hAPPxapoE mice. Neuroscience 2012 Abstracts 203.28. Society for Neuroscience, New Orleans, LA.
Summary: The hippocampus plays a key role in spatial learning and memory. Major inputs provided by the cholinergic basal forebrain (CBF) and the entorhinal cortex (EC) neurons are expected to modulate hippocampal functions. Surprisingly, the selective lesion of one or the other produces only moderate performance degradation in spatial navigation tasks, suggesting possible compensation provided by other hippocampal inputs. We therefore assessed the effects of single versus combined lesions of the EC (NMDA excitotoxin) and the CBF (mu-p75 saporin immunotoxin) on several forms of memory in C57BL/6 mice. Single lesions had moderate or no effects, while the combined lesions completely abolished long-term spatial memory retention in the water-maze and the Barnes-maze navigation tasks. Object recognition memory was selectively and profoundly affected by the loss of cholinergic neurons, whereas object location memory was only marginally affected by the lesions. These results suggest that the integrity of both the CBF and the EC is critical to establish an enduring spatial navigation memory. The synergistic interaction between the two lesions is particularly relevant to Alzheimer’s disease (AD) since both structures undergo severe degeneration in parallel to dramatic impairments in spatial navigation tasks. The apolipoprotein E4 (apoE4) allele, a major genetic risk factor for AD, has been proposed as a cholinergic deficit predictor and has been associated with larger EC atrophy in AD patients. Thus, the effects of single and combined EC and CBF lesions were evaluated on Barnes maze navigation performance in hAPPxapoE mice knocked-in for the human apoE3 or apoE4 gene allele on a (normal) human APP YAC transgenic background. Long-term spatial memory performances of hAPPxapoE3 and hAPPxapoE4 mice were dramatically affected by the CBF lesion and the combined lesions, but not by the EC lesion. A similar pattern of deficit was observed on learning performances in apoE4 not in apoE3 mice; the latter were only affected by the combined lesions. In conclusion, the apoE4 genotype had no effect on the consequences of EC and combined lesions, but it worsened the outcome of CBF lesions compared to the apoE3 genotype. Since the mice of the two genotypes showed similar loss of cholinergic neurons, our data may reflect a deleterious impact of apoE4 on the activity of the few surviving neurons (about 20%). Alternatively, our findings would also be consistent with impaired compensatory mechanisms following cholinergic loss which could depend on other hippocampal inputs such as the entorhinal cortex. Further analyses are underway to clarify this issue.
Related Products: mu p75-SAP (Cat. #IT-16)