engleski

Massive post-adolescent circuitry reorganization in the human prefrontal cortex

Development of cortical synapses is characterized by synaptic overproduction, phenomena related to the stage (time-window) of an experience-dependent reshaping (synaptic pruning) of cortical circuits. Stabilization of synaptic number at adult level is a final step in brain maturation. Available data in macaque monkey and human neocortex show synaptic overproduction in period from infancy through childhood until puberty, at which point the synaptic number settles very close to the adult values (Rakic P et al., 1994). However, affective modulation of emotional cues, as well as changes of self-concept, mentalizing, cognitive flexibility and working memory functions, continue to develop during adolescence. Also, a number of functional and imaging brain studies have demonstrated a protracted development of the human cerebral cortex beyond the puberty (Chugani HT, 2006 ; Olson EA and M Luciana, 2008). Using Golgi sections of brain tissue from the Zagreb Neuroembryological Collection we found that in large layer IIIC cortico-cortical and large layer V cortico-subcortical projection neurons in the human prefrontal cortex, dendritic spine overproduction (spines bearing excitatory glutamatergic synapses) is present from early childhood through entire adolescence until the third decade of life (Kostović I et al., 2008 ; Petanjek Z et al., 2008). Developmental reorganization of synaptic circuitry in early adulthood is so far not described in any other region of the human brain, nor in any other species. Our data are in accordance with results of several developmental studies that described changes of synaptic markers in human prefrontal cortex: i.e., synaptophysin and postsynaptic density of protein 95, complexin and N-methyl-D-aspartate-type glutamate receptors. Experimental data in the monkey brain have suggested that reorganization of intracortical excitatory systems occurred between puberty and adulthood, whereas the cortico-cortical fibers are already mature at puberty. At the other hand, thalamo-cortical fibers seem to establish circuitry arrangement much earlier (Kostović I et al., 2008). In addition, data reported here suggest also that layer IIIC associative pyramidal neurons display a greater synaptic overproduction than layer V pyramidal neurons. In these neurons the most distal oblique segments, predominantly innervated by intracortical fibers (Fuster J, 2008 ; Petanjek Z et al., 2008), have largest and most protracted overproduction. The very protracted development until adolescence was also suggested for dopaminergic innervation of the primate and human prefrontal cortices, whereas dopaminergic fibers terminate especially abundantly on layer IIIC pyramidal neurons, that also continue with fine chemical maturation until the age of 20 years (Brown RM et al., 1979). In conclusion, we demonstrate that in the human frontal cortex there is a uniquely protracted period of post-adolescent synaptic reorganization. Data support the view that protracted development through late childhood and adolescence is related with neuronal maturation and synaptic reorganization of circuitries which are essential for processing higher cognitive functions. The special emphasis for protracted cognitive development might be related to maturation of layer IIIC pyramidal neurons, that also encompasses a unique pattern of dendritic growth during early childhood (Petanjek Z et al., 2008). Besides biomedical and societal implications, these results also point to very protracted environmentally-driven plasticity in associative frontal cortex that influences circuitry development, suggesting how and for how long the environment reshapes synaptic organization.

cognition; schizophrenia; development; working memory; theory of mind

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