Updating the Lamellar Hypothesis of Hippocampal Organization

Abstract

Andersen et al. (1971) proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a “trisynaptic circuit” lying within transverse hippocampal “slices” or “lamellae.” In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the “lamellar” distribution of dentate granule cell axons (the mossy fibers), which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly “lamellar” mossy fiber pathway. The existence of pathways with “translamellar” distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis (Amaral and Witter, 1989). We suggest that the functional implications of longitudinally projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate “lateral” inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar organization.

Interlamellar CA1 network in the hippocampus

“…As noted, longitudinal interconnections are well known to exist among CA3 pyramidal cells and dentate gyrus mossy cells, but the likelihood of significant interconnections among CA1 cells has been considered "negligible" (13). Does their existence necessarily conflict with the lamellar hypothesis of hippocampal organization put forward by Andersen et al (11)?…”

“…Amaral and Witter (12) argue that, indeed, the longitudinal connectivity directly contradicts the lamellar hypothesis. In contrast, Sloviter and Lømo (13) argue that it is what the longitudinal connections actually do, their functional impact, that is the most important factor, and that a lamella should not be defined in strictly anatomical terms. For example, if the longitudinal projections were mainly targeted to inhibitory A low level of glutamate is first diffusely released by photolysis on a single basal dendrite to create a population of NMDA receptors in the "bound-butblocked" state.…”

“…(B) LTP can be induced in synapses of the longitudinal network in response to a brief high frequency stimulus (100 Hz). interneurons (26), then excitation of principal cells would create zones of lateral inhibition that would, in effect, sharpen the functional borders of the lamellae and support, rather than contradict, the lamellar hypothesis (13). Alternatively, they suggest that longitudinal connections could simply serve to coordinate activity across lamellae.…”

“…1C), depending on the actual physiological influence that these branches exert on their target cells (see ref. 13 for discussion).…”

“…This hypothesis suggests that the hippocampus is organized as a stack of parallel, trisynaptic circuits. Although this view has been challenged by the observation of fibers running across lamellae, especially in dentate gyrus and CA3 area (12,13), the hypothesis supported an explosion in the use of the transverse slice for electrophysiological studies of the hippocampus. However, axons oriented along the longitudinal axis are unavoidably severed in the preparation of the transverse slice, meaning that these studies are heavily weighted in favor of conclusions based on fibers traveling within the transverse plane.…”