Synaptogenesis in the Prefrontal Cortex of Rhesus Monkeys

Abstract

Since the turn of the century, the prefrontal association areas of the cerebral cortex have been thought to be among the last regions of the cortical mantle to develop. We have examined the course of synaptogenesis in the macaque prefrontal cortex by quantitative electron microscopic analysis in 25 rhesus monkeys ranging in age from embryonic day 47 (E47) to 20 years of age. A series of overlapping electron micrographs spanning the whole cortical thickness in each animal provided data on the number, the proportion, and the density of synapses per unit area (NA) and per unit volume (NV) of neuropil. The tempo and kinetics of synapse formation in prefrontal cortex closely resemble those described for sensory and motor areas, particularly during the stages of synapse acquisition and overproduction (Rakic et al., 1986). In young embryos, we describe a precortical phase (E47-E78), when synapses are found only above and below, but not within, the cortical plate. Following that, there is an early cortical phase, from E78 to E104, during which synapses accumulate within the cortical plate, initially exclusively on dendritic shafts. The next rapid phase of synaptogenesis begins at 2 months before birth and ends approximately at 2 months after birth, culminating with a mean density of 750 million synapses per cubic micrometer. This accumulation is largely accounted for by a selective increase in axospine synapses in the supragranular layers. The period of explosive synaptic density is followed by a protracted plateau stage that lasts from 2 months to 3 years of age when synaptic density remains relatively constant. The final period of decline, from 3 years through over 20 years of age, is marked by a slight but statistically significant decline in synaptic density. Concurrent recruitment of synapses with that of sensory and motor areas supports the concept that the initial establishment of cortical circuitry is governed by general mechanisms common to all areas, independent of their specific functional domain. The finding that synaptic density is relatively stable from early adolescence through puberty (the plateau period) is indicative of the importance, in primates, of a consistent and high synaptic density during the formative years when learning experiences are most intense.

The Basics of Brain Development

“…At the macroscropic level, studies of both monkeys and humans have documented widespread exuberant production of connections throughout all brain regions in the early postnatal period (Zecevic et al 1989;Bourgeois and Rakic 1993;Bourgeois et al 1994;Huttenlocher and de Courten 1987;Huttenlocher and Dabholkar 1997). Across brain areas, the number of synapses plateaus at levels nearly twice as high as those observed in the adult brain, and then slowly declines to normal adult levels across the period of childhood and adolescence (see Fig.…”

Prolonged coexistence of transient and permanent circuitry elements in the developing cerebral cortex of fetuses and preterm infants

“…Towards the end of gestation, neuronal circuits within the cortical plate gradually develop, as revealed by the significant increase in synaptogenesis 31 and accelerated maturation of cortical plate neurons. 4 However, these changes are probably not caused just by the relocation of synaptogenesis from the subplate zone into the cortical plate, but also by the functional change of γ-aminobutyric acid (GABA) from excitatory to inhibitory.…”

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

“…These late developmental refinements coincide with the ability to perform higher cognitive tasks (Fuster 2002) and the coming "on line" of the frontal cortex (Goldman-Rakic 1987). Taken together, these studies suggest that cortical circuitry is being refined late in childhood and early adolescence to allow for the efficient processing necessary for adult cognition.Previous postmortem studies have shown that synaptic density in cortical association areas increases after birth, peaking in early childhood and then exhibits late developmental reductions, or "pruning" in the human (Huttenlocher 1979;Huttenlocher and Dabholkar 1997) and the non-human primate (Rakic et al 1986;Bourgeois et al 1994), reaching adult levels in late adolescence or early adulthood. Similarly, the density of dendritic spines on cortical pyramidal neurons also declines by as much as 50% during this developmental period in non-human primates (Anderson et al 1995).…”

“…Accordingly, it is the synapses onto spines that have been shown to be selectively eliminated after birth (Zecevic et al 1989). In contrast, axodendritic synapse density does not change appreciably after birth and does not show this same dynamic pattern of development (Bourgeois et al 1994).Previous studies in the non-human primate suggest that synapses develop at the same rate in different cortical layers (Rakic et al 1986;Bourgeois et al 1994). In contrast, studies by Huttenlocher and Dabholkar (Huttenlocher and Dabholkar 1997) suggest that synaptogenesis occurs later in layers 2 and 3 than in layers 4-6 in the middle frontal gyrus of the human.…”