How do barrels form in somatosensory cortex?

Abstract

The somatosensory cortex of many rodents, lagomorphs, and marsupials contains distinct cytoarchitectonic features named "barrels" that reflect the pattern of large facial whiskers on the snout. Barrels are composed of clustered thalamocortical afferents relaying sensory information from one whisker surrounded by cell-dense walls or "barrels" in layer 4 of the cortex. In many ways, barrels are a simple and relatively accessible canonical cortical column, making them a common model system for the examination of cortical development and function. Despite their experimental accessibility and popularity, we still lack a basic understanding of how and why barrels form in the first place. In this review, we will examine what is known about mechanisms of barrel development, focusing specifically on the recent literature using the molecular-genetic power of mice as a model system for examining brain development.

Figure 1

Barrels can be visualized by cytochrome oxidase (CO) and Nissl histochemistry. (A) CO staining in flattened tangential section through layer 4 showing the barrel field. (B) Nissl histochemistry showing postsynaptic layer 4 neurons segregate into barrels with cell-dense walls and cell-sparse hollows. (C) The spatial arrangement of whiskers on the face are recapitulated in the brain stem as “barrelettes,” in the thalamus as “barreloids,” and in the somatosensory cortex as “barrels.”

Figure 2

Schematic barrel phenotypes in various mutant mice. (A) Barrel pattern in wildtype (WT) mice. Blue is thalamocortical (TC) axons clustered in the center of barrels (similar to the CO pattern). Orange is layer 4 cortical neurons arranged into barrels, which ring the TC afferent clusters. (B) In a group of barrel mutants, such as Cx-NR1 knock out (KO), mGluR5 KO, PLC-β KO, and PKARIIβ KO mice, TC axon clustering into a barrel pattern is intact (blue), but layer 4 barrel walls are missing (orange). (C) In a group of severe barrel mutants, all barrel features appear to be missing, including TC afferent clustering and layer 4 barrel walls. Mutants of this type include AC1 KO, 5-HTT KO, MAO KO, GAP-43 KO, NF1 KO, NeuroD2 KO, and Cx LMO4 KO mice. Note that no known mutant has intact layer 4 (Nissl) barrels but absent TC afferent (CO) barrels.

Figure 3

Pre- and postsynaptic mechanisms of barrel map formation at thalamocortical synapses. Presynaptic: action potentials activate voltage-gated Ca2+ channels (VGCC). The increase in Ca2+ concentration at axon terminals triggers glutamate neurotransmitter release. Intracellular Ca2+ also activates adenylyl cylase 1 (AC1), which catalyzes the formation of cAMP. cAMP, in turn, activates PKA. PKA regulates neurotransmitter release directly via the phosphorylation of RIM1α.61 In addition, PKA may regulate thalamocortical axon clustering into a barrel pattern via changes in the expression of a number of proteins through modulation of nuclear transduction. 5-HT at the synaptic cleft is released by nerve terminals originating in the raphe nuleus. 5-HT can be transported into the axon terminal by 5-HTT and packaged into vesicles by VMAT2. Excess intracellular 5-HT is degraded by MAOA. The presence of 5-HT1B receptors on thalamocortical axon terminals, when activated by binding to extracellular 5-HT, may negatively regulate AC1 activity via G-proteins. Postsynaptic: two major signal pathways regulating barrel map formation occur in layer 4 postsynaptic neurons: AC1–cAMP–PKA and Ras–GAP–MAPK. Glutamate released from presynaptic terminals activates glutamate receptors, including mGluRs, AMPARs, and NMDARs. The simultaneous binding of glutamate and postsynaptic depolarization activates NMDARs, allowing Ca2+ to flow through NMDARs and VGCCs. The increased Ca2+ concentration thereby activates postsynaptic AC1 and PKA. PKA phosphorylates AMPARs, facilitating AMPAR traffic to the membrane. mGluR5 activates PLCβ (phospholipase C-β), which acts through the Ras–GAP–Erk(MAPK) pathway. mGluR5s may interact with the AC1–cAMP–PKA signal pathway via Gq proteins. Neurofibromatosis type 1 (NF1) is one of a family of Ras–GAP proteins that negatively regulates Ras–Erk (MAPK). Together with NeuroD2 and LMO4, signals converge into the nucleus, influencing the expression of proteins in cortical neurons responsible for their aggregation into barrel walls and orienting their dendrites toward barrel hollows.