306 A similar segregation of pyramidal cells has been observed in mice homozygous for the scrambler mutation of the Dab1 gene (Gonza´les et al. 1997; Ohshima et al. 2001), which presumably acts downstream of the reeler gene in laminar development, and in mice heterozygous for a disruption of the Lis1 gene (Hirotsune et al. 1998), which codes for the b subunit of platelet-activating factor acet- ylhydrolase. A layering of CA1 is also seen in doublecor- tin(Dcx)/Dcx-like kinase mutant mice (Deuel et al. 2006), which lack these microtubule-associated proteins required for normal cortical and hippocampal development. Lami- nation is more severely disturbed in double heterozygous Dcx/Lis1 knockout mice, which show a multi-layered dis- tribution of CA1 pyramidal cells (Pramparo et al. 2010). Notably, the ablation of both p35, an activator of cyclin- dependent kinase 5, and reelin results in a homogenous distribution of cells in stratum oriens and the pyramidal cell layer (Ohshima et al. 2001). While morphological changes extend beyond CA1, the pattern within CA1 at least resembles that seen in microchiropteran bats and primates. The different migratory capabilities of neurons in knockout mice or mice carrying natural mutations may be caused by cell-intrinsic factors other than the primary mutation, which should affect all pyramidal cells. Alter- natively, extrinsic factors, such as spatial barriers set up by ingrowing afferents (Ishida et al. 1994; Deller et al. 1999), may be responsible. Cell-intrinsic factors would per se distinguish the two populations. Extrinsic factors will, in a structure in which the laminar speciﬁcity of afferents is the most characteristic feature, distinguish the two populations functionally. Either way, to maintain the concept of homogeneity of the pyramidal cell layer becomes a more complex task. Furthermore, the aggregation of superﬁcial CA1 pyramidal cell depends on their developmental expression of Zbtb20 (Fig. 3f), a member of the BTB/POZ zinc ﬁnger family (Mitchelmore et al. 2002), without which CA1 develops a cortex-like structure (Xie et al. 2010). Misexpression of Zbtb20 in extrahippocampal neurons results in the aggregation of cells of the upper layers of adjacent subicular ﬁelds in a compact CA1-like superﬁcial layer (Nielsen et al. 2007, 2010). Zbtb20 is co-expressed with Satb2 (Nielsen et al. 2010; Xie et al. 2010), which is also required for the development of superﬁcial neocortical layers (Britanova et al. 2008). Also, Zbtb20 expression is mutually exclusive with the expression of Sox5 (Fig. 3f), which in the neocortex is necessary for the speciation of deep corticofugal neurons (Lai et al. 2008). CA3 123 Natural mutations of common laboratory species that resolve different sublayers in CA3 as strikingly as in CA1 are not known. Although sublayers are visible in illustrations of Brain Struct Funct (2011) 216:301–317 CA3 of scrambler mice (Gonza´les et al. 1997, their ﬁg- ure 3c) it has not been described whether this pattern is consistent. Milder lamination changes are present in BALB/ c, dreher mice, and weaver mice (Vaughn et al. 1977; Nowakowski 1984; Nowakowski and Davis 1985; Sekiguchi et al. 1992, 1995) and appear to affect neurons differentially according to their time of generation (Vaughn et al. 1977). More recently, a lamination defect has been described in CA3 and, to a lesser extent, in CA1 of mice carrying a targeted mutation in the Dcx gene (Corbo et al. 2002; Nosten-Bertrand et al. 2008; Kappeler et al. 2007). In these mice, ectopic CA3 pyramidal cells can be found in both stratum oriens and radiatum and may give short segments of CA3 a bilaminar appearance. A similar phenotype has been observed in knock-out mice deﬁcient in p35 (Ohshi- ma et al. 2005) and Lis1 mutant mice (Wang and Baraban 2008). A bilaminar proximal CA3 pyramidal cell layer and ectopic clusters of pyramidal cells in stratum oriens of distal CA3 have be found in Fukutin-knockout mice (Takeda et al. 2003). ‘‘Abnormalities’’ of this type can be found in distal and temporal CA3 segments of the Chin- cilla, in which pyramidal-like cells form a second cell tier in stratum oriens. Notably, at least the proximal dendrites of these ectopic cells are not targeted by mossy ﬁbers (Fig. 3g). A loosely packed band of cells also characterizes stratum oriens of distal CA3 in the fox (Fig. 3h). CA1 and CA3 CA1 lamination defects in Dcx/Dcx-like kinase double mutant mice (Deuel et al. 2006) and in a-1 tubulin mutant mice (Keays et al. 2007) extend into CA3 and appear more pronounced than those resulting from mutations in p35 or Dcx alone. Knockdown of the actin-binding protein girdin or an inhibition of the interaction of girdin with Disrupted- In-Schizophrenia1 (DISC1) result in appearance of abnor- mal layers in CA1 and CA3 (Enomoto et al. 2009). While the Fukutin-knockout alone does not affect lamination beyond CA3, it may do so in O-mannosyltransferase 2 knockout mice (POMT2, Hu et al. 2011), in which loose clusters of CA1 pyramidal cell are found beneath a compact superﬁcial layer not dissimilar to the pattern seen in possum or mole rat. Last, a distinct bilaminar pyramidal cell layer in CA1 and CA3 is seen in mice deﬁcient in microtubule-actin crosslinking factor 1a (Goryunov et al. 2010). Neurochemistry At least two substances that are selectively distributed to, in both cases, superﬁcial pyramidal cells have the potential to modulate responses of CA1 cells to afferent stimulation or to modulate the effect that CA1 efferents may have in their