Expression profiling has established a 'molecular map' of the hippocampal formation, organized over its transverse and long axes. This molecular map provides a possible substrate for regional vulnerability and can in part account for why ageing and a range of diseases target different hippocampal subregions.
Electrophysiological, functional MRI and behavioural studies have suggested a 'functional map' of the hippocampal formation, organized over its transverse and long axes. This map can explain why ageing and a range of diseases manifest with phenotypic diversity, despite targeting the same brain structure.
Perhaps surprisingly, hippocampal dysfunction can be characterized by either an abnormal hypometabolic or hypermetabolic state.
Establishing differential patterns of hippocampal vulnerability could provide information on the underlying mechanisms. For example, the fact that the entorhinal cortex is vulnerable to Alzheimer's disease but is relatively spared in cognitive ageing suggests that these conditions are mediated by separate pathogenic mechanisms.
Establishing abnormalities in metabolic state can also suggest mechanistic clues. For example, the hippocampal hypermetabolism that is observed in schizophrenia is proposed to be linked to elevations in synaptic glutamate.
Results from MRI tools that have been developed to image the hippocampal circuit have given rise to a pathophysiological framework. Newer imaging tools and large-scale longitudinal studies are expected to address outstanding issues, including mapping how ageing and disease spread over time, and providing additional insights into pathogenesis.
The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.
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S.A.Sm. is supported by US National Institute on Aging (NIA) grants AG025161, AG034618, AG034618 and AG035015, the US National Institute of Mental Health (NIMH) grant MH093398, and the James S. McDonnell Foundation. M.P.W. is supported by the Kavli Foundation and center of excellence grant from the Norwegian Research Council (Nr 145,993). C.A.B. is supported by the McKnight Brain Research Foundation and NIA grant AG003376. S.A.Sc. is supported by NIMH grant K23MH09056. We thank C. Stark, H. Eichenbaum, and I. Asllani for comments on earlier versions of this manuscript.
The authors declare no competing financial interests.
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Small, S., Schobel, S., Buxton, R. et al. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12, 585–601 (2011). https://doi.org/10.1038/nrn3085
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