NEUROCHEMICAL DEVELOPMENT OF THE HIPPOCAMPAL REGION IN THE FETAL RHESUS-MONKEY .1. EARLY APPEARANCE OF PEPTIDES, CALCIUM-BINDING PROTEINS, DARPP-32, AND MONOAMINE INNERVATION IN THE ENTORHINAL CORTEX DURING THE 1ST-HALF OF GESTATION (E47 TO E90)

Although the entorhinal cortex is a kev structure connecting the hippo campal formation with the rest of the cerebral cortex, little is known about its early chemoanatomical development in primates. In the prese nt study, a cytoarchitectonic analysis and immunocytochemical detectio n of somatostatin. neurotensin. parvalbumin, calbindin-D 28K, DARPP-32 , as well as tyrosine hydroxylase, dopamine-beta-hydroxylase, and sero tonin, were carried out on serial sections of the entorhinal cortex of six rhesus monkey fetuses aged E47 to E90 (gestation period 165 days) . Ag E56 the cortical plate of the entorhinal cortex already exhibited a sublamination; at E64 the lamina dissecans was partly formed. allow ing the emergence of the lamina principalis externa and interna, and a t E83 most of the regional and laminar subdivisions characteristic of the adult cortex could be identified, except for the rhinal sulcus res tricted to a small dimple. The neurochemical development paralleled th e early cytoarchitectonic differentiation, both largely preceding that of the neighboring cortical areas. The somatostatin-like immunoreacti ve innervation, first detected at E56, was very dense as early as E64 and displayed by E83 a laminar distribution similar to that found in t he adult. Labeled neurons indicated an intrinsic origin for this inner vation but an extrinsic connection might be present as labeled fibers in the subplate of the entorhinal cortex were in continuity with posit ive fibers in the intermediate zone of the hippocampal formation. A fa int neurotensin-like immunoreactivity first detected at E64 became pro minent at E83 in the entorhinal cortex but stopped abruptly at the anl age of the rhinal sulcus. The lack of neurotensin-labeled neurons cont rasted with their presence in other parts of the hippocampal region an d suggested a precocious extrinsic connection. Only rare parvalbumin-L IR neurons were detected at midgestation, whereas calbindin-D 28K was expressed from E47 on in Cajal-Retzius cells and from E56 on in variou s types of neurons in the cortical plate and subplate. Most characteri stic was a category of medium-sized, deeply stained calbindin-LIR neur ons, present only in the lamina principalis externa and possibly corre sponding to the population of large neurons described by Kostovic et a l. (1990, Soc Neurosci Abstr 16:846) in early developing entorhinal co rtex of human fetuses. These and probably other neurons were also DARP P-32-positive, suggesting the possibility of an early dopaminergic reg ulation. Indeed. the monoaminergic innervation of the entorhinal corte x was detected from E56 on and gradually increased in density, display ing areal and laminar differences in the distribution of the dopaminer gic, noradrenergic, and serotoninergic afferents. Each of the neuroact ive substances under study also displayed a distinct pattern with resp ect to the mediolateral and rostrocaudal organization of the entorhina l cortex. These findings reveal a remarkably early maturation of the e ntorhinal cortex during the first half of gestation, compatible with t he possibility of trophic effects. However, in keeping with the early neurochemical development of the hippocampal formation, it does not se em unreasonable to suggest that some functional circuits are already f orming in the hippocampo-entorhinal complex of primates during the fir st half of gestation.