Inhibitory local circuit neurons

Synaptic inhibition is essential to the function of diverse neural networks. Information processing in many sensory cortices depends on the balance between excitation and inhibition (Monier et al., 2003; Wehr and Zador, 2003; Wilent and Contreras, 2005), such that a stimulus-evoked increase in cortical excitatory drive is almost always matched by a compensatory increase in local inhibition. Until recently, inhibitory local circuit neurons of the PC have been little studied. However, research efforts in the last decade have shed light on 1) the diverse interneuron classes that are present in the PC (Suzuki and Bekkers, 2010a, b); 2) how interneurons are incorporated into the PC neural network (Luna and Schoppa, 2008; Stokes and Isaacson, 2010; Franks et al., 2011; Suzuki and Bekkers, 2012) and 3) how they might contribute to the processing of olfactory sensory information (Luna and Schoppa, 2008; Stokes and Isaacson, 2010; Suzuki and Bekkers, 2012; Bekkers and Suzuki, 2013).

At least five main classes of PC inhibitory interneurons have been recently characterised based on information on morphology, somatic laminar location, expression of molecular markers and electrical properties (Suzuki and Bekkers, 2010a, b). They are namely horizontal cells (HZ), neurogliaform cells (NG), bitufted cells (BT), fast-spiking multipolar cells (fMP) and regular-spiking multipolar cells (rMP; Figure 1-12B; Suzuki and Bekkers, 2010a, b).

1.4.5.1 Feedforward and feedback microcircuits

Feedforward and feedback microcircuits are the building blocks of the inhibitory network. These canonical network motifs predominate in practically all brain regions (Isaacson and Scanziani, 2011), including the PC (Figure 1-12A; Stokes and Isaacson 2010; Suzuki and Bekkers, 2012). The two inhibitory pathways operate synergistically and contribute to the patterning of principal neuron output, coincidence detection and network oscillations.

HZ and NG cells of layer 1a have locally ramifying dendritic and axonal arbours (Stokes and Isaacson, 2010; Suzuki and Bekkers, 2010b). They receive direct sensory input from the OB and mediate short-latency, disynaptic feedforward inhibition of principal neurons (Figure 1-12A, IN1; Luna and Schoppa, 2008; Stokes and Isaacson,

2010, Suzuki and Bekkers, 2012). In contrast, fMP cells of layer 3 do not receive direct sensory input as their dendritic and axonal arbours are restricted to the associational layers (Stokes and Isaacson, 2010; Suzuki and Bekkers, 2010b, 2012). Instead, fMP cells are activated by intracortical recurrent fibers and mediate powerful feedback inhibition of nearby principal neurons via perisomatic contacts (Figure 1-12A, IN2).

In this way, fMP cells are reminiscent of parvalbumin-expressing basket cells found in the hippocampus and other neocortical regions (Somogyi et al., 1998; Markram et al., 2004; Freund and Katona, 2007).

The contributions of BT, rMP and NG cells located in the associational layers are less clear-cut. These interneurons likely receive a mixture of bulbar and recurrent inputs and as such, they are likely implicated in feedforward and feedback inhibition to different degrees. Nevertheless, the subcellular domains targeted by these interneurons could be deduced from their axonal arbours. For example, rMP cells appear to target mostly dendrites and probably provide predominantly dendritic inhibition, whereas BT cells are more likely to provide somatic inhibition (Suzuki and Bekkers, 2010b).

Figure 1-12 PC inhibitory network

A. Two types of canonical inhibitory microcircuits have been identified in the PC. Interneurons implicated in the feedforward pathway (IN1) receive direct sensory input and mediate dendritic

inhibition of principal neurons. In contrast, interneurons implicated in the feedback pathway (IN2) are activated by intracortical recurrent fibers and mediate predominantly somatic

inhibition. B. At least five classes of inhibitory interneurons have been identified in the PC. HZ, horizontal cell; NG, neurogliaform cell; BT, bitufted cell; FS, fast-spiking multipolar cell; RS, regular-spiking multipolar cell. Part A was adapted from Suzuki and Bekkers (2012) and part B was adapted from Bekkers and Suzuki (2013).

1.4.5.2 Dynamic inhibition

A recent study showed that in response to bursts of LOT activity similar to M/T cell output during olfactory stimuli (Cang and Isaacson, 2003; Margrie and Schaefer, 2003), layer 1 interneurons provide early-onset, transient dendritic inhibition of principal neurons, which effectively enforces late temporal integration of bursting inputs (Stokes and Isaacson, 2010). In contrast, layer 3 fMP cells preferentially fire late during bursting input and mediate late-onset somatic inhibition (Stokes and Isaacson, 2010). The authors therefore suggested that synaptic inhibition shifts from the dendrite to the soma of principal neurons in response to sensory stimulation (Stokes and Isaacson, 2010). As sensory synapses are uniquely localised to the apical dendritic layer in the PC, it is thought that the apparent dendro-somatic routing of inhibition makes intuitive sense, as it follows the flow of olfactory sensory information, from a region of synaptic integration to a region of spike output (Stokes and Isaacson, 2010).

In contrast, Suzuki and Bekkers showed that each of the three PC cortical laminae contains at least two types of functionally distinct interneurons, providing either early-onset or late-onset inhibition in response to naturalistic bursting input (Suzuki and Bekkers, 2010b). These results indicate that the five identified classes of interneurons appear to be differentially engaged in phasic inhibition in a layer- specific manner in response to simulated odour stimulation. The authors therefore suggested that the different types of interneurons are ideally poised to provide temporally precise inhibition at different phases of the respiratory cycle (Suzuki and Bekkers, 2010b).

Interestingly, empirical data indicate that SL and SP cells are differentially affected by synaptic inhibition. In response to simulated feedback inhibition, LOT-evoked spiking is powerfully inhibited in SP cells but not in SL cells (Suzuki and Bekkers, 2012). These results further reinforce the functional distinction between the two classes of principal neurons.