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 twoto 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.association cortex | critical period | schizophrenia | synaptogenesis

Tourette's syndrome (TS) is a genetically influenced developmental neuropsychiatric disorder characterized by chronic vocal and motor tics. We studied Slit and Trk-like 1 (SLITRK1) as a candidate gene on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with TS. Among 174 unrelated probands, we identified a frameshift mutation and two independent occurrences of the identical variant in the binding site for microRNA hsa-miR-189. These variants were absent from 3600 control chromosomes. SLITRK1 mRNA and hsa-miR-189 showed an overlapping expression pattern in brain regions previously implicated in TS. Wild-type SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Collectively, these findings support the association of rare SLITRK1 sequence variants with TS.

The polarity and adhesion of radial glial cells (RGCs), which function as progenitors and migrational guides for neurons, are critical for morphogenesis of the cerebral cortex. These characteristics largely depend on cadherin-based adherens junctions, which anchor apical end-feet of adjacent RGCs to each other at the ventricular surface. Here, we show that mouse numb and numb-like are required for maintaining radial glial adherens junctions. Numb accumulates in the apical end-feet, where it localizes to adherens junction-associated vesicles and interacts with cadherins. Numb and Numbl inactivation in RGCs decreases proper basolateral insertion of cadherins and disrupts adherens junctions and polarity, leading to progenitor dispersion and disorganized cortical lamination. Conversely, overexpression of Numb prolongs RGC polarization, in a cadherin-dependent manner, beyond the normal neurogenic period. Thus, by regulating RGC adhesion and polarity, Numb and Numbl are required for the tissue architecture of neurogenic niches and the cerebral cortex.

Pyramidal neurons of the cerebral cortex display marked layer-and subtype-specific differences in their axonal projections and dendritic morphologies. Here we show that transcription factor Zfp312 is selectively expressed by layer V and VI subcortical projection pyramidal neurons and their progenitor cells. Knocking down Zfp312 with small interfering RNAs dramatically reduced the number of subcortical axonal projections from deep-layer pyramidal neurons and altered their dendritic morphology. In contrast, misexpression of Zfp312 in cortically projecting pyramidal neurons of layers II and III induced the expression of Tbr1, a transcription factor enriched in deep-layer neurons, and the formation of ectopic subcortical axonal projections. Thus, our results indicate that transcription factor Zfp312 plays a critical role in layer-and neuronal subtype-specific patterning of cortical axonal projections and dendritic morphologies.development ͉ neocortex ͉ transcription factor T he development of the cerebral cortex requires the correct molecular specification of neuronal identity and the proper formation of neuronal connections. The majority of cortical neurons are pyramidal neurons, which extend long axonal projections both within and beyond the cortex (1-3). Pyramidal neurons display marked layer-and subtype-specific differences in their axonal projections and dendritic morphologies (1-6). The axons of pyramidal neurons in layers II and III form synaptic connections solely with other cortical neurons. In contrast, the majority of layer V and VI pyramidal neurons project axons to subcortical targets, comprising the collective output of the cortex. Layer VI pyramidal neurons project to the thalamus, whereas other subcortical regions, including the brainstem and spinal cord, receive cortical projections mainly from layer V pyramidal neurons.Cortical progenitor cells give rise to pyramidal neurons in an inside-first, outside-last sequential manner (3, 6-8). Deep-layer neurons originate from early progenitors in the ventricular zone (VZ), whereas upper-layer neurons arise from late progenitors. Although laminar position is normally correlated with the type of axonal projection, it is not laminar position but the timing of neuron generation that determines the axonal target (3,(6)(7)(8). Cortical progenitors at the earliest stage of neurogenesis are multipotent, exhibiting the ability to generate multiple types of pyramidal neurons (8). Later in neurogenesis, the developmental potential of these progenitors becomes progressively restricted to the generation of only upper-layer neurons (8). It has been proposed that genetic programs control this restriction process. However, active molecular determinants for the generation and differentiation of deep-layer neurons remain unknown.Layer-and neuronal subtype-specific molecular markers, many of which are transcription factors, have been identified in the cerebral cortex (3,(9)(10)(11)(12). To explore the molecular development of deep-layer pyramidal neurons, we started with gen...