Membrane-associated molecules regulate the formation of layer-specific cortical circuits

Abstract

The columnar organization of the mammalian neocortex is based on radially oriented axon collaterals which precisely link cells from distinct cortical layers. During development, these interlaminar connections are specific from their initial outgrowth: collaterals form only in the target layers and there are no transient axonal collaterals in the nontarget layers. To examine whether positional cues within individual cortical layers regulate the laminar specificity of collateral formation, explants of cells destined for different cortical layers were cultured on membranes prepared from target and nontarget layers. Axonal growth and branching were examined on homogeneous membrane substrates and on alternating stripes of membranes from different layers. Results show that axons branch preferentially on membrane substrates from those layers that they would target in vivo. In addition, when cortical axons were given a choice to grow on membranes from either their target or their nontarget layer, they exhibited a clear preference for the target layers. This indicates that membrane-associated cues confined to individual layers regulate the formation of collaterals of cortical axons and restrict their growth to their target layers. Heat inactivation of membranes from target layers resulted in reduced axonal branching. The same manipulation of membranes from nontarget layers increased axonal branching for one population of cortical neurons. Taken together, these results suggest that membrane-associated molecules confined to individual layers induce and prevent the formation of axon collaterals in distinct populations of cortical neurons. Thus, the expression of layer-specific cues provides important constraints for the remodeling of local circuits during cortical development.A prominent component of the intrinsic circuitry of the neocortex are collateral connections of axons from pyramidal and spiny stellate cells. Within one cortical layer, tangentially oriented collaterals form regular clusters of axonal branches (1-3) and interconnect cells with similar functional specificities (4-6). In the vertical domain, pyramidal neurons have a main axon that projects out of the cortex and makes local connections within some of the 6 cortical layers (7-11) For instance, the axons of pyramidal cells in layers 2͞3 give rise to tangentially oriented collaterals in layers 2͞3 and layer 5 that branch profusely within these layers but do not extend into the adjacent layers 4 or 6 (see Fig. 1 A). On the other hand, many pyramidal cells in layer 6 send their efferent axon back to the thalamus. These axons emit collaterals in layer 6, which ascend to branch in the overlaying layers 4 and 3. As axon collaterals of layer 6 cells traverse layer 5 they make very few branches in this layer. Physiological studies in primary visual cortex revealed that this precise pattern of interlaminar connections generates characteristic response properties of cortical neurons (12)(13)(14).During development, collateral clusters within a cortical layer...

Inhibitory Mechanism by Polysialic Acid for Lamina-Specific Branch Formation of Thalamocortical Axons

“…To date it has been shown that retinal axons preferentially form branches in appropriate layers of fixed tectal tissues (Yamagata and Sanes, 1995) or in the membrane fraction obtained from the corresponding tectal region (Roskies and O'Leary, 1994). Cortical neurons have also been shown to form branches preferentially on membrane obtained from particular layers (Castellani and Bolz, 1997). These findings are consistent with the present results for the thalamocortical projection.…”

Neurotrophin-4/5 Alters Responses and Blocks the Effect of Monocular Deprivation in Cat Visual Cortex during the Critical Period

“…Finally, an increase in nonspecific connections might cause responses to preferred and nonpreferred stimuli to regress toward the mean response to all stimuli, decreasing peak, but not total, responsiveness. It has been argued that promiscuous sprouting would cause thalamocortical transneuronal label to spread beyond layer IV, which has not been seen, but in fact other chemical clues may constrain axons to the appropriate layer (Castellani and Bolz, 1997). These experiments with high concentrations do not directly address a role for endogenous NT-4/5.…”

Development of layer-specific axonal arborizations in mouse primary somatosensory cortex

“…Previous studies strongly suggest that molecular cues are used by developing pyramidal neurons to establish their initial layer-specific axonal arbors (Bolz and Castellani, 1997;Castellani and Bolz, 1997;Castellani et al, 1998;Dantzker and Callaway, 1998;Butler et al, 2001;Borrell and Callaway, 2002). A distinct neuronal class would respond differently to cues found within layer 4 and arborize within this layer where growth of axons from other layer 2/3 pyramidal neurons is excluded.…”