Extraordinary neoteny of synaptic spines in the human prefrontal cortex

Abstract

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.

Fig. 1.

(A) Representative low-magnification photographs of the rapid Golgi-impregnated layer IIIc and V pyramidal cells in the dorsolateral prefrontal cortex of a 16-y-old subject. Black arrows indicate basal dendrites, and gray arrows indicate oblique dendrites. (Scale bar: 100 μm.) (B) Neurolucida reconstruction of layer IIIc pyramidal neuron of a 49-y-old subject, illustrating sites selected for counting spines over a 50-μm length of apical distal oblique dendrites (green), apical proximal oblique dendrites (blue), and basal dendrites (red). (Scale bar: 100 μm.) (C) Representative high-power magnification images of rapid Golgi-impregnated layer IIIc pyramidal neurons from the dorsolateral prefrontal cortex showing basal dendrites (Left) and distal apical oblique dendrites (Right) during different stages: an infant 1 mo of age, a 2.5-y-old child, and 16-y-old, 28-y-old, and 49-y-old subjects. (Scale bar: 10 μm.) (D) Graphs representing number of dendritic spines per 50-μm dendrite segment on basal dendrites after the first bifurcation (red); apical proximal oblique dendrites originating within 100 μm from the apical main shaft (blue); and apical distal oblique dendrites originating within the second 100-μm segment from the apical main shaft (green) of layer IIIc (filled symbols) and layer V (open symbols) pyramidal cells in the dorsolateral prefrontal cortex. Squares represent males; circles represent females. The age in postnatal years is shown on a logarithmic scale. Puberty is marked by a shaded bar. B, birth (fourth postnatal day); P, puberty. Specification of tissue analyzed is given in Table S1, and the positions of sections on which pyramidal neurons were measured are indicated on the reconstructed pyramidal neuron shown in B.

Fig. 2.

The DSD, as defined in Fig. 1, plotted at the linear scale to illustrate the dynamics of changes occurring during the 100-y human lifespan. Regression curves fit the distribution of data from the basal dendrites (A), apical proximal oblique dendrites (B), and apical distal oblique dendrites (C) of pyramidal cells from layer IIIc and V. In all cases the equation of the curves is a double exponential function in the form: y = a*exp(−bt)+c*exp (−dt)+e, where a, b, c, d, and e are fixed coefficients, and t is time in years (Table S3).