SummarySensory computations performed in the neocortex involve layer six (L6) cortico-cortical (CC) and cortico-thalamic (CT) signaling pathways. Developing an understanding of the physiological role of these circuits requires dissection of the functional specificity and connectivity of the underlying individual projection neurons. By combining whole-cell recording from identified L6 principal cells in the mouse primary visual cortex (V1) with modified rabies virus-based input mapping, we have determined the sensory response properties and upstream monosynaptic connectivity of cells mediating the CC or CT pathway. We show that CC-projecting cells encompass a broad spectrum of selectivity to stimulus orientation and are predominantly innervated by deep layer V1 neurons. In contrast, CT-projecting cells are ultrasparse firing, exquisitely tuned to orientation and direction information, and receive long-range input from higher cortical areas. This segregation in function and connectivity indicates that L6 microcircuits route specific contextual and stimulus-related information within and outside the cortical network.

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SummaryTo interpret visual-motion events, the underlying computation must involve internal reference to the motion status of the observer’s head. We show here that layer 6 (L6) principal neurons in mouse primary visual cortex (V1) receive a diffuse, vestibular-mediated synaptic input that signals the angular velocity of horizontal rotation. Behavioral and theoretical experiments indicate that these inputs, distributed over a network of 100 L6 neurons, provide both a reliable estimate and, therefore, physiological separation of head-velocity signals. During head rotation in the presence of visual stimuli, L6 neurons exhibit postsynaptic responses that approximate the arithmetic sum of the vestibular and visual-motion response. Functional input mapping reveals that these internal motion signals arrive into L6 via a direct projection from the retrosplenial cortex. We therefore propose that visual-motion processing in V1 L6 is multisensory and contextually dependent on the motion status of the animal’s head.

NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis.DOI: http://dx.doi.org/10.7554/eLife.06953.001

Oligodendrocyte precursor cells (OPCs) are the major source of myelinating oligodendrocytes during development. These progenitors are highly abundant at birth and persist in the adult where they are distributed throughout the brain. The large abundance of OPCs after completion of myelination challenges their unique role as progenitors in the healthy adult brain. Here we show that adult OPCs of the barrel cortex sense fine extracellular K ϩ increases generated by neuronal activity, a property commonly assigned to differentiated astrocytes rather than to progenitors. Biophysical, pharmacological, and single-cell RT-PCR analyses demonstrate that this ability of OPCs establishes itself progressively through the postnatal upregulation of Kir4.1 K ϩ channels. In animals with advanced cortical myelination, extracellular stimulation of layer V axons induces slow K ϩ currents in OPCs, which amplitude correlates with presynaptic action potential rate. Moreover, using paired recordings, we demonstrate that the discharge of a single neuron can be detected by nearby adult OPCs, indicating that these cells are strategically located to detect local changes in extracellular K ϩ concentration during physiological neuronal activity. These results identify a novel unitary neuron-OPC connection, which transmission does not rely on neurotransmitter release and appears late in development. Beyond their abundance in the mature brain, the postnatal emergence of a physiological response of OPCs to neuronal network activity supports the view that in the adult these cells are not progenitors only.

NG2 cells, a main pool of glial progenitors, express γ-aminobutyric acid A (GABA(A)) receptors (GABA(A)Rs), the functional and molecular properties of which are largely unknown. We recently reported that transmission between GABAergic interneurons and NG2 cells drastically changes during development of the somatosensory cortex, switching from synaptic to extrasynaptic communication. Since synaptic and extrasynaptic GABA(A)Rs of neurons differ in their subunit composition, we hypothesize that GABA(A)Rs of NG2 cells undergo molecular changes during cortical development accompanying the switch of transmission modes. Single-cell RT-PCR and the effects of zolpidem and α5IA on evoked GABAergic currents reveal the predominance of functional α1- and α5-containing GABA(A)Rs at interneuron-NG2 cell synapses in the second postnatal week, while the α5 expression declines later in development when responses are exclusively extrasynaptic. Importantly, pharmacological and molecular analyses demonstrate that γ2, a subunit contributing to the clustering of GABA(A)Rs at postsynaptic sites in neurons, is down-regulated in NG2 cells in a cell type-specific manner in concomitance with the decline of synaptic activity and the switch of transmission mode. In keeping with the synaptic nature of γ2 in neurons, the down-regulation of this subunit is an important molecular hallmark of the change of transmission modes between interneurons and NG2 cells during development.

In the postnatal central nervous system, glial cells expressing the chondroitin sulfate proteoglycan NG2 (NG2-cells) constitute a cell population exhibiting several properties of oligodendrocyte precursors such as the ability to proliferate. One particular feature of NG2-cells is that they express several glutamatergic and GABAergic ionotropic receptors activated by synaptic neurotransmitter release. Here, we used patch-clamp recordings, immunostaining, calcium imaging, and intracellular labeling to test for the presence of ionotropic nicotinic acetylcholine receptors (nAChRs) in NG2-cells identified in acute hippocampal slices of mice. We demonstrated that these cells express functional nAChRs during the second postnatal week, i.e., the period in which they become the most abundant proliferative cell type of CA1 stratum radiatum. Pharmacological experiments showed that NG2-cells express alpha 7-containing nAChRs. In particular, the powerful positive allosteric modulator of these receptors PNU-120596 induced a 20-fold increase of agonist-induced currents and revealed rises in intracellular calcium concentration upon agonist applications. In addition, nanomolar concentrations of nicotine, which did not induce any response in these cells, largely desensitized nAChR-mediated currents. These data indicate that the functional expression of Ca(2+)-permeable alpha 7-containing nAChRs in hippocampal slices is not restricted to neurons and that the receptors of NG2-cells can be desensitized by low concentrations of nicotine.

The major types of glial cells-astrocytes, microglia, and cells of the oligodendroglial lineage-are known to express functional metabotropic and ionotropic GABA receptors. Neuronal signaling mechanisms allowing for the activation of these receptors in glia are probably as complex as those described among neurons and involve synaptic and extrasynaptic transmission modes. In addition, astrocytes can signal back to neurons by releasing GABA, probably through unconventional nonvesicular mechanisms. The decryption of the roles played by GABAergic signaling in neuron-glia interactions is only beginning, but it has been suggested that activation of glial cells by GABA influences important functions of the brain such as neuronal activity, differentiation, myelination, and neuroprotection. This review discusses the cellular mechanisms allowing the major types of glial cells to sense and transmit GABAergic signals and gives an overview of potential roles of this signaling pathway in developing and mature brains.