Brain Struct Funct (2011) 216:301–317 DOI 10.1007/s00429-011-0322-0 R E V I E W Hippocampal pyramidal cells: the reemergence of cortical lamination Lutz Slomianka • Irmgard Amrein • Irene Knuesel • Jens Christian Sørensen • David P. Wolfer Received: 11 March 2011 / Accepted: 26 April 2011 / Published online: 20 May 2011 The Author(s) 2011. This article is published with open access at Springerlink.com Abstract The increasing resolution of tract-tracing studies has led to the deﬁnition of segments along the transverse axis of the hippocampal pyramidal cell layer, which may represent functionally deﬁned elements. This review will summarize evidence for a morphological and functional differentiation of pyramidal cells along the radial (deep to superﬁcial) axis of the cell layer. In many species, deep and superﬁcial sublayers can be identiﬁed histologically throughout large parts of the septotemporal extent of the hippocampus. Neurons in these sublayers are generated during different periods of develop- ment. During development, deep and superﬁcial cells express genes (Sox5, SatB2) that also specify the phenotypes of superﬁcial and deep cells in the neocortex. Deep and super- ﬁcial cells differ neurochemically (e.g. calbindin and zinc) and in their adult gene expression patterns. These markers also distinguish sublayers in the septal hippocampus, where they are not readily apparent histologically in rat or mouse. Deep and superﬁcial pyramidal cells differ in septal, striatal, and neocortical efferent connections. Distributions of deep L. Slomianka (&) I. Amrein D. P. Wolfer Institute of Anatomy, University of Zu¨rich, 8057 Zu¨rich, Switzerland e-mail: slomianka@anatom.uzh.ch I. Knuesel Institute of Pharmacology and Toxicology, University of Zu¨rich, Zu¨rich, Switzerland J. C. Sørensen Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark D. P. Wolfer Institute of Anatomy and Zu¨rich Center for Integrative Human Physiology, University of Zu¨rich and Institute of Human Movement Sciences, ETH Zu¨rich, Zu¨rich, Switzerland and superﬁcial pyramidal cell dendrites and studies in reeler or sparsely GFP-expressing mice indicate that this also applies to afferent pathways. Histological, neurochemical, and connective differences between deep and superﬁcial neurons may correlate with (patho-) physiological phenomena speciﬁc to pyramidal cells at different radial locations. We feel that an appreciation of radial subdivisions in the pyramidal cell layer reminiscent of lamination in other cortical areas may be critical in the interpretation of studies of hippocampal anatomy and function. Keywords Hippocampus CA1 CA3 pathways Calbindin Efferent pathways Development Physiology Zinc Afferent Introduction Traditionally the hippocampal pyramidal cell layer is divided into a number of subﬁelds along its transverse extent from its proximal end close to the area dentata to its distal limit adjacent to the subiculum. On the basis of the absence or presence of the layer harboring the mossy ﬁbers, the earliest subdivision recognized two ﬁelds, regio supe- rior and regio inferior (Ramo´ n y Cajal 1893). Later Golgi- studies reﬁned this division, resulting in the recognition of several subﬁelds and adoption of the CA1a-c–CA2–CA3a- c nomenclature (Lorente de No´ 1934). The topographical organization of projections from CA3 to CA1 (Ishizuka et al. 1990), from CA1 to the subiculum (Tamamaki and Nojyo 1991; Tamamaki et al. 1987; Amaral et al. 1991) and, ﬁnally, from CA1 and the subiculum to extrahippo- campal sites (Witter et al. 1990; Namura et al. 1994; Tamamaki and Nojyo 1995; Risold and Swanson 1996; Blatt and Rosene 1998) have given credence to the 123