Abstract
The recurrent network composed of excitatory and inhibitory neurons is fundamental to neocortical function. Inhibitory neurons in the mammalian neocortex are molecularly diverse, and individual cell types play unique functional roles in the neocortical microcircuit. Recently, vasoactive intestinal polypeptide-positive (VIP+) neurons, comprising a subclass of inhibitory neurons, have attracted particular attention because they can disinhibit pyramidal cells through inhibition of other types of inhibitory neurons, such as parvalbumin- (PV+) and somatostatin-positive (SOM+) inhibitory neurons, promoting sensory information processing. Although VIP+ neurons have been reported to receive synaptic inputs from PV+ and SOM+ inhibitory neurons as well as from cortical and thalamic excitatory neurons, the somatodendritic localization of these synaptic inputs has yet to be elucidated at subcellular spatial resolution. In the present study, we visualized the somatodendritic membranes of layer (L) 2/3 VIP+ neurons by injecting a newly developed adeno-associated virus (AAV) vector into the barrel cortex of VIP-Cre knock-in mice, and we determined the extensive ramification of VIP+ neuron dendrites in the vertical orientation. After immunohistochemical labeling of presynaptic boutons and postsynaptic structures, confocal laser scanning microscopy revealed that the synaptic contacts were unevenly distributed throughout the perisomatic (<100 μm from the somata) and distal-dendritic compartments (≥100 μm) of VIP+ neurons. Both corticocortical and thalamocortical excitatory neurons preferentially targeted the distal-dendritic compartment of VIP+ neurons. On the other hand, SOM+ and PV+ inhibitory neurons preferentially targeted the distal-dendritic and perisomatic compartments of VIP+ neurons, respectively. Notably, VIP+ neurons had few reciprocal connections. These observations suggest different inhibitory effects of SOM+ and PV+ neuronal inputs on VIP+ neuron activity; inhibitory inputs from SOM+ neurons likely modulate excitatory inputs locally in dendrites, while PV+ neurons could efficiently interfere with action potential generation through innervation of the perisomatic domain of VIP+ neurons. The present study, which shows a precise configuration of site-specific inputs, provides a structural basis for the integration mechanism of synaptic inputs to VIP+ neurons.
Highlights
In the neocortex, γ-aminobutyric acid-ergic (GABAergic) inhibitory neurons display a large diversity of dendritic and axonal morphologies, intrinsic firing properties and chemical characteristics (Markram et al, 2004; Ascoli et al, 2008; Kubota, 2014; Zeisel et al, 2015; Tasic et al, 2016)
Our quantitative imaging analyses focused on the distribution of synaptic inputs to L2/3 VIP+ neurons in the S1BF at subcellular resolution and revealed that synaptic inputs to VIP+ neurons had preferences for certain somatodendritic compartments, similar to the pattern of innervation to pyramidal cells (Figure 10)
The present findings show a precise configuration of site-specific inputs to VIP+ neurons
Summary
Γ-aminobutyric acid-ergic (GABAergic) inhibitory neurons display a large diversity of dendritic and axonal morphologies, intrinsic firing properties and chemical characteristics (Markram et al, 2004; Ascoli et al, 2008; Kubota, 2014; Zeisel et al, 2015; Tasic et al, 2016). Most L2/3 VIP+ neurons extend their dendrites bidirectionally in the vertical orientation, morphologically characterized as bipolar/modified bipolar/bitufted cells, and send axon fibers vertically and translaminarly across L1–6 (Connor and Peters, 1984; Kawaguchi and Kubota, 1996; Bayraktar et al, 2000; Prönneke et al, 2015). Activation of VIP+ neurons potentiates the excitability of pyramidal cells through inhibition of other types of inhibitory neurons innervating pyramidal cells, which have been found mainly in L2/3 of sensory cortices (Lee et al, 2013; Pfeffer et al, 2013; Pi et al, 2013; Fu et al, 2014; Zhang et al, 2014). The activity regulation of L2/3 VIP+ neurons is crucial for the gain control of pyramidal cell response to sensory inputs in sensory cortices (Kepecs and Fishell, 2014; Pfeffer, 2014)
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