THE HUMAN ENTORHINAL CORTEX Anatomic Organization and Its Alteration in Alzheimer ’ s Disease and Temporal Lobe Epilepsy

The human entorhinal cortex is located in the ventromedial portion of the temporal lobe and consists of eight subfields. It has reciprocal connections with the hippocampus and various other cortical and subcortical structures, and thus forms an integral component of the medial temporal lobe memory system. The entorhinal cortex is damaged in the early stages of Alzheimer’s disease (AD) and also in temporal lobe epilepsy (TLE). The present studies characterize the normal neuronal organization of the human entorhinal cortex using calcium-binding protein immunohistochemistry (e.g., parvalbumin, calretinin, and calbindin D28k, hereafter referred to as calbindin) and lucifer yellow microinjections. Moreover, the changes in the entorhinal neuronal populations containing the three calcium-binding proteins are described for AD. The reorganization processes in the entorhinal cortex and in its hippocampal target areas in normal and diseased brain were also studied with the aid of highly polysialylated neural cell adhesion molecule (PSA-NCAM), which is abundantly expressed in the developing brain, as well as in brain areas that undergo continuous remodeling. The major findings of these studies were: 1A) The distribution of calcium-binding proteins largely followed the cytoarchitectonic borders of the eight subfields of the entorhinal cortex. Parvalbumin neurons were morphologically interneurons. Although calretinin and calbindin were localized in non-pyramidal cells, they also labeled some pyramidal-like neurons. The high density of non-pyramidal neurons containing these calciumbinding proteins in layers II and III suggests they form a critical network that controls entorhinal outputs to the hippocampus. In addition, their largely non-overlapping distribution suggests that each neuron type modulates a different subset of topographically-organized entorhinal outputs. 1B) Based on the shape of the somata and primary dendritic trees, spiny neurons were divided into classical pyramidal, stellate, modified stellate, and horizontal tripolar cells. Vertical extension of the dendritic branches to adjacent layers supports the idea that inputs terminating in specific layers influence target cells located in various entorhinal laminae. There is more overlap in the dendritic fields of layers II and III than between the superficial and deep layers, which supports the idea of segregation of information flow targeted to superficial or deep layers of the human entorhinal cortex. 2) In AD, the most profound neuronal loss and neurofibrillary tangle formation was observed in the intermediate, lateral, and caudal subfields of the entorhinal cortex. Parvalbuminand calbindin-containing non-pyramidal neurons were morphologically altered early in the entorhinal pathology, whereas calretinin-containing nonpyramidal cells were morphologically better preserved. Our findings suggest that the specific subfields and layers of the entorhinal cortex that contain distinct calcium-binding proteins are differentially vulnerable. This might impact the topographically-organized inputs and outputs of the entorhinal cortex. 3) In the entorhinal cortex, the major changes in PSA-NCAM immunoreactivity were observed in layers II and III of AD and TLE patients when compared to controls. In hippocampus, the PSA-NCAM immunoreactivity in the outer molecular layer of the dentate gyrus was increased in AD, whereas the inner third of the molecular layer had major changes in TLE. In TLE cases with mild overall neuronal loss in the hippocampus and in AD, the number of PSA-NCAM positive infragranule cells was increased whereas no PSA-NCAM positive infragranule cells were observed in cases with severe hippocampal damage in TLE. Whether the loss of granule cells in TLE is related to the reduced capacity for granule cells to differentiate remains to be explored. Taken together, the human entorhinal cortex is formed of neurochemically heterogeneous subfields in which information flow is presumably differentially modulated by local interneurons. The pathologic changes occuring in AD and TLE do not involve the entire entorhinal cortex to the same extent, and some neuronal types are more vulnerable than others. In addition, the reorganization of neuronal circuitries takes place in the entorhinal cortex and in its hippocampal target areas in AD and TLE. National Library of Medicine Classification: WL 359, WL 385 Medical Subject Headings: Alzheimer’s disease; entorhinal cortex; hippocampus; epilepsy, temporal lobe; neuronal plasticity; calcium-binding protein/analysis; nerve fibers; calretinin/analysis; calbindin/analysis; parvalbumin/analysis; NCAM/analysis Nec scire fas est omnia. Horatius (65-8 B.C.)