Brain Struct Funct (2011) 216:301–317 suggested that these classes may correspond to deep and superﬁcial pyramidal cells. Similarly, late depolarizing postsynaptic potentials in response to commissural or Schaffer collateral stimulation were observed in only one (L-type) of two classes of septal CA1 pyramidal cells (Fan et al. 2005) that have dendritic distributions similar to the superﬁcial pyramids described by Bannister and Larkman (1995). In addition to the regulation of the response character- istics of cells to afferent stimulation, calbindin may also inﬂuence transmission presynaptically by impeding paired- pulse facilitation until Ca2?-buffer saturation (Blatow et al. 2003; Dumas et al. 2004). This may distinguish the way in which deep and superﬁcial CA1 pyramidal cells can affect their targets. This is also true for zinc, the second neuro- chemical that distinguishes superﬁcial and deep pyramidal cells. Zinc affects a vast array of ligand- and voltage-gated ion channels (Frederickson et al. 2005). Prominent among zinc effects is a potent modulation of both NMDA and non- NMDA glutamate receptor function (Paoletti et al. 2009) through interactions with subunit speciﬁc zinc-binding sites (Paoletti et al. 2000; Rachline et al. 2005). How antago- nistic effects on NMDA receptors and agonistic effects on AMPA and kainate receptors translate into models of hippocampal function will depend on the functional con- nectivity of the zinc-containing deep CA3 and superﬁcial CA1 pyramidal cells. A radial difference in the physiology of guinea pig CA3 pyramidal cells is a preference for burst-type ﬁring cells to be located in the deep part of the cell layer (Bilkey and Schwartzkroin 1990). Cells with different ﬁring charac- teristics may correspond to those distinguished morpho- logically in rats by Fitch et al. (1989). An earlier study (Masukawa et al. 1982) reported a preferential location of these cells in proximal CA3. Overlapping neurogenetic gradients distributing different pyramidal cells types along both transverse and radial gradients may explain this discrepancy. A study in the Guaira spiny rat is the only one in which the physiological properties of deep and superﬁcial pyra- midal cells have been systematically investigated in a CA1 showing a dense superﬁcial layer above a zone of loosely distributed pyramids that spans much of the stratum oriens (Scorza et al. 2011). Deep pyramidal cells located in the stratum oriens showed distinctly higher membrane capac- itance, latency to ﬁre at threshold and rheobase, but a lower input resistance and depolarizing sag than superﬁcial pyramidal cells. Pathology and pathophysiology Tabuchi et al. (1995) observed degenerative changes preferentially in deep CA1 pyramidal cells after short 311 periods of ischemia in Japanese macaques. A preferential degeneration of deep CA1 pyramidal cells was also observed during early postnatal development in rabbits as a consequence of pilocarpine-induced seizures (Towﬁghi et al. 2004). A higher incidence of depolarizing responses to anoxia has been found in rat deep CA1 pyramidal cells when compared with superﬁcial cells (Morris et al. 1995). Differential effects of ischemia on CA1 pyramidal cells of the L- and non-L-types (Fan et al. 2005) have also been observed (Ruan et al. 2007). Some of these observations would be compatible with a neuroprotective role of calbindin (Scharfman and Schwartzkroin 1989; Mattson et al. 1991; Guo et al. 1998). However, superﬁcial pyramidal cells in rabbits do not contain calbindin, and CA1 pyramidal cells of calbindin- knockout mice were more resistant to overt ischemia than their counterparts in wild-type mice (Klapstein et al. 1998). That additional factors are likely to be involved is sug- gested by (1) the differential response of deep and super- ﬁcial rabbit CA1 cells, neither of which contain calbindin and (2) the survival of both superﬁcial and deep cells in the calbindin-knockout mice, in which only superﬁcial cells should be immediately affected. One, two or more? Based on this short review we feel that it is very difﬁcult to maintain the concept of pyramidal cell homogeneity along the radial axis of the cell layer. Rather it seems that in many species distinct deep and superﬁcial populations of pyramidal cells can be identiﬁed, which differ in neuro- chemistry, connectivity, and their reactions to selective pressures exerted during the phylogeny of particular spe- cies. Examples of features distinguishing superﬁcial and deep CA1 pyramidal cells are summarized in Fig. 6. A similar division of CA3 pyramidal cells may be superim- posed on stronger proximo-distal gradients. How many layers should we then recognize? Gene expression studies, zinc and calbindin suggest that even the compact pyramidal cell layer of the septal hippocampus can be divided into two sublayers. Further temporally and in distal CA1, they appear to be supplemented by a third, deep sublayer, which again can be characterized by the presence of calbindin and a distinct gene expression pat- tern. In some respects these layers reﬂect principles of neocortical organization with small superﬁcial cells main- taining connections to nearby cortical areas, while deep cells are mainly responsible for long-distance intercortical and subcortical telencephalic communication. Analogizing hippocampal and neocortical layers came easy to Schaffer (1892), who could state that the laminar organization of the CA ﬁelds completely reﬂected that of ‘‘typical cortex’’, and 123