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Review
. 2016 Jul 20;91(2):260-92.
doi: 10.1016/j.neuron.2016.06.033.

GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits

Robin Tremblay  1 , Soohyun Lee  1 , Bernardo Rudy  2
Affiliations
Review

GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits

Robin Tremblay et al. Neuron. .

Abstract

Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.

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Figures

Figure 1
Figure 1. Diversity, classification and properties of neocortical GABAergic interneurons
Nearly all the INs in neocortex express one of the main three, non-overlapping, markers: Parvalbumin (PV, blue), somatostatin (Sst, red) and the ionotropic serotonin receptor 5HT3a (5HT3aR, green-yellow). Further subdivisions within each molecular group are revealed by morphological features, cellular and subcellular targeting biases, the expression of other markers, as well as some known anatomical, electrophysiological and synaptic properties.
Figure 2
Figure 2. Laminar distribution of IN groups
GABAergic interneurons are unevenly distributed within the cortical mantle. The PV group is a major component throughout the cortex, except in L1, where it is virtually absent. Sst neurons are found in all layers, most prominently in infragranular layers. 5HT3aR INs dominate in supragranular layers, however there is a clear laminar separation between VIP-expressing INs, the largest population in L2/3 and non-VIP interneurons, which represent ~ 90% of L1 INs. These laminar distributions are from mouse somatosensory cortex, but very similar distributions have been found in frontal and visual cortices (see (Xu et al., 2010) for comparison).
Figure 3
Figure 3. Cell-specific connectivity and subcellular domains targeted by interneuron subtypes
(A) Main known connectivity of INs to L2/3 pyramidal cells. The two major IN subtypes targeting dendrites are Sst Martinotti cells (red) and non-Vip 5HT3aR neurogliaform cells (dark yellow). Both L2/3 and L5 Martinotti cells have been shown to connect to L2/3 PCs (Jiang et al., 2015; Kapfer et al., 2007). Since their axons target both L2/3 and L1, it is assumed that supra- and infragranular Martinotti INs are positioned to contact basal, apical and tuft dendrites. L1 and L2/3 NGFCs are known to have axonal arbors largely restricted to their own layer and thus basal and apical dendrites are expected to be targeted by L2/3 NGFCs while tuft dendrites should be contacted by L1 NGFCs (Hestrin and Armstrong, 1996; Jiang et al., 2015; Kawaguchi and Kubota, 1997; Wozny and Williams, 2011). The perisomatic region and proximal dendrites are targeted by Cck basket cells (light yellow) and PV fast-spiking basket cells (dark blue). The axon initial segment is contacted by PV chandelier cells (light blue). Although connections by Vip bipolar cells onto PC soma and proximal dendrites have been reported (Kawaguchi and Kubota, 1997; Meskenaite, 1997), the connectivity is relatively weak with low probability. (B) Main connectivity onto L5/6 pyramidal cells. L2/3 Martinotti cells only poorly contact infragranular PCs (Jiang et al., 2015; Jiang et al., 2013) thus among Martinotti cells only those in infragranular layers target L5 PCs. In contrast, L1, L2/3 and L5/6 NGFCs contact L5 PC dendrites. Perisomatic and axonal contacts are provided by infragranular basket and chandelier cells. (C) Main inhibitory connections among INs. NGFCs target all interneuron subtypes and thus their connectivity is solely restricted by the extent of their axonal arbor (Jiang et al., 2015). Martinotti cells contact all IN subtypes except other Sst INs (Pfeffer et al., 2013). Input and output connectivity of neocortical Cck basket cells with other INs has not been investigated, however it is assumed that they receive inputs from both Martinotti cells and NGFCs. PV basket cells are known to strongly connect to other PV cells. Although connections from PV cells to other INs have been reported, conflicting data exists in the literature and have thus been omitted here. Vip bipolar cells are selective for other interneurons, particularly Sst INs. L2/3 bipolar Vip INs can contact both L2/3 and L5 Sst INs. While the connectivity of infragranular Vip cells has not been investigated, it is assumed to show similar cell type selectivity than supragranular Vip INs and be restricted to deep layers given that their axons do not ascend to supragranular layers (Bayraktar et al., 2000; Pronneke et al., 2015). Only the general connectivity patterns of the most well-known cell types are illustrated in this figure. It should also be noted that that many PC subtypes exists in every layer and although some PC subtype-specific connectivity by INs has been shown, this has not been thoroughly investigated and therefore has been omitted.
Figure 4
Figure 4. Circuit motifs involving INs
In feedforward inhibition (top), an external source makes excitatory synapses (arrows) onto both local principal cells (PC) and interneurons (IN). Interneurons in turn provide inhibitory inputs (black dot) to PCs. Feedback inhibition (middle) occurs when the source of excitation is local. INs can in turn make inhibitory synapses on the local PCs that provided the excitation (recurrent) or other neighboring PCs that did not participate in the recruitment of the IN (lateral). In disinhibition (bottom), the principal target of an IN is another interneuron, preventing it from inhibiting PCs.
Figure 5
Figure 5. Thalamocortical FFI by PV neurons imposes coincidence detection
A. Thalamocortical neurons synapse onto both excitatory principal cells (PC) and PV neurons. Thalamocortical connections are stronger onto PV than PC neurons. B. FFI by PV INs curtails TC mediated EPSPs on PCs leaving a narrow temporal window of opportunity for excitatory inputs to summate. Consequently, near synchronous inputs are required for efficient summation of EPSPs and to drive action potential firing on the PC. C. Weakening of PV INs FFI by short-term depression of TC synaptic inputs onto PV cells and PV INs outputs to PC (Gabernet et al., 2005). These two steps of adaptation weaken FFI more than direct feed-forward excitation of PC neurons. D. Weakening of FFI by modulation of PV IN output synapses. Both GABAB receptor-activation by NGFCs (Chittajallu et al., 2013) and muscarinic receptor-activation by acetylcholine (Kruglikov and Rudy, 2008) reduce inhibitory outputs to PCs. E. Relationship between the summation of EPSPs on PCs and their temporal difference for different strengths of FFI. As FFI is weakened, asynchronous inputs can summate more effectively (Pouille and Scanziani, 2001). F. FFI regulates the gain of PC populations. As excitatory drive increases, PV cells recruitment increases at a higher rate than the recruitment of excitatory cells. This will prevent PC population from saturation and will allow a wider dynamic range of the local PC population than if inhibition was absent (dotted line) (Pouille et al., 2009).
Figure 6
Figure 6. Feedback inhibition (FBI) and differential effect of PV and Sst INs-mediated inhibition
A. FBI circuit motif encompassing both recurrent and lateral feedback inhibition. B. PV and Sst interneurons differentially summate excitatory inputs from local PCs. PV neurons (top), due to their low input resistance, fast membrane time constant and depressing excitatory inputs show a decrease in spike probability upon repetitive excitation (left) and are thus synchrony detectors, requiring the near coincident action of different cells to spike (right) (Silberberg, 2008; Silberberg and Markram, 2007). In contrast, Sst INs (bottom) have a high input resistance, slow membrane time constant and facilitating excitatory inputs and therefore show an increase in spike probability upon repetitive stimulation. This makes Sst neurons sensitive to individual excitatory cell’s firing rate and bursting (Kapfer et al., 2007; Silberberg, 2008; Silberberg and Markram, 2007). C. Assembly competition and synchronization of local PCs by PV neurons. Synchronously active PCs will recruit PV neurons that will then inhibit the local population (Silberberg, 2008).. D. Assembly competition and ‘winner takes all’ circuit mechanism with Sst INs FBI (Silberberg, 2008). By following the most active PC(s), an Sst IN will prevent the activation of other neighboring cells (except other Sst INs). E. Perisomatic inhibition by PV INs regulates the timing of action potentials (Royer et al., 2012). The speed and effectiveness at which PV INs perform this task imposes short temporal windows for excitation to generate action potentials within the local population, thus favoring their synchronization (Cobb et al., 1995). In contrast, dendritic targeting bias of Sst INs regulates input integration at the dendrite and dendritic electrogenesis such as NMDA and calcium spikes that can generate burst firing (Larkum et al., 1999).
Figure 7
Figure 7. VIP interneuron-mediated disinhibition
A. VIP INs show high target selectivity for Sst INs which results in disinhibition of the dendrites of pyramidal cells when VIP INs are active (Jiang et al., 2015; Pfeffer et al., 2013; Pi et al., 2013). B. Widespread activation of this disinhibitory circuit could have a broad influence on the state of excitability of an area and is thought to be mediated by neuromodulators (see text). C. Given the narrow and vertical extent of VIP IN dendrites and axons (Pronneke et al., 2015), their recruitment by excitatory inputs showing topographic organization can mediate spatially localized sites of disinhibition, as in (Zhang et al., 2014). Such inputs are thought to originate from glutamatergic afferents from the thalamus and top-down corticocortical projections (see text).
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