The perforant path: projections from the entorhinal cortex to the dentate gyrus

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Abstract

This paper provides a comprehensive description of the organization of projections from the entorhinal cortex to the dentate gyrus, which together with projections to other subfields of the hippocampal formation form the so-called perforant pathway. To this end, data that are primarily from anatomical studies in the rat will be summarized, complimented with comparative data from other species. The analysis of the organization of any of the connections of the hippocampus, including that of the entorhinal cortex to the dentate gyrus, is severely hampered because of the complex three-dimensional shape of the hippocampus. In particular in rodents, but to a lesser extent also in primates, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis. To amend this, we will describe own unpublished tracing data obtained in the rat with the use of the so-called extended preparation. A number of issues will be addressed. First, data will be summarized which will clarify the laminar origin of the perforant pathway within the entorhinal cortex. Second, we will discuss whether or not a radial organization, along the proximo-distal dendritic axis of granule cells, characterizes the entorhinal-dentate projection. Third, we will discuss whether this projection is governed by any transverse organization, and fourth, we will focus on the organization along the longitudinal axis. Finally, the synaptic organization and the contralateral entorhinal-dentate projection will be described briefly. Taken together, the available data suggest that the projection from the entorhinal cortex to the dentate gyrus is a fairly well conserved connection, present in all species studied, exhibiting a grossly similar organization.

Introduction

A description of the projection from the entorhinal cortex to the dentate gyrus is an indispensable part of any work on the dentate gyrus for at least two reasons. First, this pathway, generally referred to as the perforant pathway, provides the dentate gyrus with its major cortical input. Second, the perforant pathway is among the pathways in the brain that have been most actively investigated, beginning with the earliest pioneers in neuroscience who described its remarkable structure and organization. These studies were followed by others, which clarified the central importance of the perforant pathway to hippocampal function and plasticity, studies which continue to this day.

The elaborate Golgi studies of Ramón y Cajal (1911) and Lorente de Nó (1933), first demonstrated that the entorhinal cortex is the origin of an immensely strong projection to the dentate gyrus. These observations were subsequently corroborated and extended in a seemingly continuous stream of tracing studies using axonal degeneration techniques (Blackstad, 1958; Hjorth-Simonsen, 1972; Hjorth-Simonsen and Jeune, 1972), followed by transport of radioactively labeled amino acids and horseradish peroxidase (Van Hoesen and Pandya, 1975; Steward, 1976; Wyss, 1981; Witter and Groenewegen, 1984; Witter, 1989; Witter et al., 1989b) and finally the more recently introduced sensitive tracing with lectines and dextran-amines (Köhler, 1985; Witter, 1989; Tamamaki and Nojyo, 1993; Deller et al., 1996; Deller, 1998). In the same period, a number of retrograde tracing studies, again using a variety of different tracers, have further contributed to our current understanding of the entorhinal-dentate projection (Ruth et al., 1982, Ruth et al., 1988; Witter et al., 1989b; Dolorfo and Amaral, 1998). Although the dentate gyrus is the “traditional” target of the entorhinal-hippocampal fibers, there is ample evidence that the entorhinal cortex also projects to the hippocampal fields CA1–CA3, and to the subiculum (Steward, 1976; Steward and Scoville, 1976; Witter et al., 1989a; Desmond et al., 1994; Naber et al., 2001; Baks-Te-Bulte et al., 2005).

In all species, the hippocampus and entorhinal cortex show a complex three-dimensional orientation and relationship. In rats in particular, this has lead to a general tendency to restrict hippocampal and entorhinal studies to those parts that are most easily accessible, such as dorsal hippocampus and central parts of entorhinal cortex. Initially this resulted in rather coarse descriptions of the overall functionality and connectivity of entorhinal-dentate relationships, and it was only after analyses started to include the full extent of both entorhinal cortex and dentate gyrus that we became aware of the complex topographical organization of this connection. It is now more widely appreciated that the hippocampus and entorhinal cortex are not as homogeneous in their organization as initially conceived, (cf. Witter and Groenewegen, 1990). A major reason for this new perspective was the use of tools to circumvent a major problem with hippocampal studies in rodents, the fact that the hippocampal formation and the entorhinal cortex are curved structures. Cutting through such curved structures in any plane will result in sections that at some point or another do not cut through the hippocampus and entorhinal cortex at an angle that is perpendicular to the respective long axes. Initially described by Gaarskjaer (1978), and advocated by Ishizuka (2001), and likewise by Amaral and Witter (1989), this problem can be amended by using the so-called extended preparation, and in a number of studies this approach has resulted in improved understanding of the connectional organization of the system (Amaral and Witter, 1989; Ishizuka et al., 1990; Ishizuka, 2001).

Many of the disputes about functions of the entorhinal-dentate projection, and entorhinal-hippocampal connectivity more generally, are likely to be related to this spatial problem, at least in part. A proper understanding of the complex three-dimensional organization of the system is essential to evaluate data from functional studies which suggest heterogeneity, as has been suggested for the dorsal versus the ventral hippocampus, for example (Witter et al., 1989a; Moser et al., 1993). Another, more recent example deals with the rather confusing data addressing the functional relevance of the entorhinal cortex. Here, again, studies have benefited significantly from taking into account the complex three-dimensional organization of cortico-entorhinal-hippocampal connections (Fyhn et al., 2004; Hafting et al., 2005; Hargreaves et al., 2005; Steffenach et al., 2005; Sargolini et al., 2006). Over the years, one of our aims has been to further our understanding of the system through systematic descriptions of its complex anatomical organization. For the present paper, the focus will be on the entorhinal-dentate projection; in a recently published parallel paper, the focus was on entorhinal projections to the subiculum (Witter, 2006). The data support a currently prevailing view that there are two differentially organized components within the entorhinal-dentate projection, originating from the lateral and medial entorhinal cortex respectively.

Section snippets

Dentate gyrus

In all species, the dentate gyrus represents part of the cortex situated closest to the free rim of the original cortical anlage, but the final position and overall structural organization of the dentate gyrus and of the hippocampus as a whole may be quite different among species (Stephan, 1975; Voogd et al., 1998). To give a striking example, one just has to compare the position of the hippocampus in the rat with that in primates. In the rat the structure extends from a dorsomedial position,

Fiber pathways

After leaving the entorhinal cortex, perforant path fibers enter the underlying white matter and the angular bundle. They then traverse the pyramidal cell layer of the subiculum and cross the hippocampal fissure to enter the dentate gyrus, or distribute to the molecular layer of the subiculum and the hippocampus. The entorhinal cortex fibers also take alternative routes such as projecting through the alveus before entering the hippocampus, or by traversing the molecular layers of the entorhinal

Layers of origin in the entorhinal cortex

In rat, mouse, or monkey, the ipsilateral projection to the dentate gyrus appears to arise mainly, if not exclusively from layer II of the entorhinal cortex (Steward and Scoville, 1976; Schwartz and Coleman, 1981; Ruth et al., 1982, Ruth et al., 1988; Witter et al., 1989b; van Groen et al., 2003; Chrobak and Amaral, 2006). In humans, fetal material indicates a similar origin (Hevner and Kinney, 1996). It is of interest to note that in the brain of Alzheimer patients, the entorhinal cortex layer

Radial or layered terminal organization in the dentate gyrus

One of the more convincing arguments to differentiate between the lateral and medial subdivisions of the entorhinal cortex, aside from overall cytoarchitectonic differences, was based on observations that fibers originating in the LEC terminate in the outer one-third of the molecular layer and fibers from the MEC terminate in the middle one-third of the molecular layer (Hjorth-Simonsen and Jeune, 1972; Hjorth-Simonsen, 1972). This initial idea was strengthened further by the striking laminar

Transverse organization in the dentate gyrus

There are conflicting papers on the transverse distribution of the perforant path projection. In earlier studies no differences were reported (Hjorth-Simonsen, 1971, Hjorth-Simonsen, 1972; Hjorth-Simonsen and Jeune, 1972; Steward, 1976). Wyss (1981) reported that the lateral perforant pathway preferentially projects to the enclosed blade of the dentate gyrus, whereas the medial component either does not show a preference or predominantly targets the exposed blade. It should be stressed,

Longitudinal organization of entorhinal-dentate projections

Entorhinal projections show a striking organization along the longitudinal axis of the dentate gyrus. Originally described in the cat (Witter and Groenewegen, 1984), it was later discovered to be a general governing principle in all species studied (Ruth et al., 1982, Ruth et al., 1988; Witter et al., 1989b; Dolorfo and Amaral, 1998; van Groen et al., 2003). In the rat, cells located laterally in the entorhinal cortex project to dorsal parts of the dentate gyrus while cells located

Contralateral projections

In the rat, the entorhinal cortex projects to the ipsilateral dentate gyrus, and also gives rise to a crossed projection to the contralateral dentate gyrus, as well as the contralateral CA3 and CA1 subfields, and the subiculum. The crossed entorhinal projection is most prominent to the more dorsal portions of the hippocampal subfields and rapidly diminishes in density at more temporal levels (Goldowitz et al., 1975; Steward, 1976). With respect to the laminar origin of the crossed projections,

Synaptic organization of the entorhinal-dentate projection

In the molecular layer of the dentate gyrus in the rat, the terminals of the perforant path fibers in the outer two-thirds of the molecular layer make up at least 85% of the total synaptic population (Nafstad, 1967; Matthews et al., 1976). Entorhinal fibers form mainly, if not exclusively, asymmetric synapses (Nafstad, 1967; Matthews et al., 1976; Deller and Leranth, 1990; Leranth et al., 1990). These occur most frequently on the dendritic spines of dentate granule cells, although a small

Summary and functional comments

The main origin of the projection from the entorhinal cortex to the dentate gyrus is throughout layer II cells in EC. Entorhinal axons of layer II cells have their terminals predominantly, if not exclusively, in the outer two-thirds of the molecular layer of the dentate gyrus. An additional projection arises from cells in deeper layers of the entorhinal cortex, mainly deep V and VI. In the rat, and likely in the mouse as well, these deeply located cells appear to be the source of most if not

Acknowledgments

This paper is based on large quantities of work carried out by many colleagues over the years. I am greatly indebted to them and their well-prepared publications on this subject. Moreover, for the experimental data described, I owe my former technician, Mrs. B. Jorritsma-Byham, who performed most of the analyses, assisted by a sizable group of under-graduate students. Dr. G. Doctor developed the statistical routines and performed the measurements on the radial position of terminal fields.

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