Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci U S A

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10,000 Zagreb, Croatia.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 108(32):13281-6. DOI: 10.1073/pnas.1105108108
Source: PubMed


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.

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    • "Likewise, structural changes associated with synaptic pruning may underlie the diffuse-tofocal shift in FC patterns reported here, contributing to the refinement of the proprioceptive network. Several studies on humans (Huttenlocher 1979; Huttenlocher and Dabholkar 1997; Petanjek et al. 2011) and nonhuman primates (Rakic et al. 1986, 1994; Bourgeois et al. 1994) have reported that synapse and dendritic spine loss, which starts at 4/5 years of age and continues up to adulthood, applies to the entire cerebral cortex as regard both the different cortical layers (e.g., layers III and V that contain cortico-cortical and cortico-subcortical projecting pyramidal neurons , respectively) and the different brain regions (e.g., the somatosensory, motor, and prefrontal cortices). Accordingly, a parallel exists between the ubiquitous aspect of synaptic pruning that covers the entire cerebral cortex and the diffuse-to-focal shift in FC that applies to the variety of cortical and subcortical regions of the proprioceptive network. "
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    ABSTRACT: Proprioceptive processing is important for appropriate motor control, providing error-feedback and internal representation of movement for adjusting the motor command. Although proprioceptive functioning improves during childhood and adolescence, we still have few clues about how the proprioceptive brain network develops. Here, we investigated developmental changes in the functional organization of this network in early adolescents (n = 18, 12 ± 1 years), late adolescents (n = 18, 15 ± 1), and young adults (n = 18, 32 ± 4), by examining task-evoked univariate activity and patterns of functional connectivity (FC) associated with seeds placed in cortical (supramarginal gyrus) and subcortical (dorsal rostral putamen) regions. We found that although the network is already well established in early adolescence both in terms of topology and functioning principles (e.g., long-distance communication and economy in wiring cost), it is still undergoing refinement during adolescence, including a shift from diffuse to focal FC and a decreased FC strength. This developmental effect was particularly pronounced for fronto-striatal connections. Furthermore, changes in FC features continued beyond adolescence, although to a much lower extent. Altogether, these findings point to a protracted developmental time course for the proprioceptive network, which breaks with the relatively early functional maturation often associated with sensorimotor networks.
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    • "This suggests either a high safety factor for maintaining hyperpolarizing GABAergic responses in mature mammalian cortical principal neurons (see Diamond 2002; Puskarjov et al. 2014a) or that the further increase in KCC2 protein serves to facilitate the ion transport-independent functions of KCC2 in synaptogenesis. These 2 scenarios are mutually nonexclusive, and the latter is consistent with the notion that the peak synaptogenic period in humans takes place during infancy/early childhood (Huttenlocher and Dabholkar 1997; Petanjek et al. 2011) and in the rodent cortex after the ontogenetic shift to hyperpolarizing GABA A R signaling (Juraska 1982; De Felipe et al. 1997; Fiumelli et al. 2013). Notably, immature rodent hippocampal neurons have the capacity to optimize their use of the available KCC2 levels via increased membrane Figure 6. "
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    ABSTRACT: Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl(-) extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca(2+)-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.
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    • "Post-mortem brain studies in the 1970s and 1980s had shown that synaptic density, which corresponds to the number of connections ( " synapses " ) between neurons observed per unit of neuronal surface, increases drastically in the first few months and years of life and then progressively decreases during childhood in the visual and auditory cortex, and during adolescence in the prefrontal cortex (Huttenlocher, 1979; Huttenlocher & Dabholkar, 1997; see Petanjek et al., 2011 for more recent data). Despite this evidence for early dendritic arborisation and later prolonged pruning of synaptic connections, it was until recently widely held that the brain was anatomically mature during adolescence, and that changes in social behaviour during this period of life were a result of hormones, social experience, and the changing social environment. "
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    ABSTRACT: This article describes recent research which informs our understanding of changes in social cognition during adolescence. The focus will be on mentalising, the ability to attribute and manipulate mental states in the self and others. Mentalising is supported by the medial prefrontal cortex (MPFC) and both anterior and posterior regions of the temporal lobes. In the past decade, studies have demonstrated development during adolescence of white and grey matter brain structure, with most protracted changes observed in frontal and temporal lobes, including those regions supporting mentalising. This article presents evidence that certain aspects of social cognition continue to change during adolescence, highlighting results from recent research investigating the use of theory of mind information in a communicative context. The findings highlight how adolescence, and not only childhood, is a time of continued maturation of brain and behaviour, when education and the environment can have an impact on cognitive development.
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