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ScienceDirect Cell-type specific function of GABAergic neurons in layers 2 and 3 of mouse barrel cortex Carl CH Petersen GABAergic neurons are a minor fraction of the neocortical neuronal population, but they are highly diverse in their features. The GABAergic neurons can be divided into three largely nonoverlapping groups, defined through the expression of ionotropic serotonin receptors, parvalbumin or somatostatin. Membrane potential recordings from these genetically defined GABAergic neurons in layers 2 and 3 of mouse barrel cortex reveal that they are differentially modulated by whisker behavior. As a mouse begins to explore its environment by actively moving its whiskers, motor-related signals drive different activity patterns in specific types of GABAergic neurons, thereby promoting sensorimotor integration. The neural circuit mechanisms underlying such cell-type specific activity of GABAergic neurons are now being unraveled. Addresses Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Switzerland Corresponding authors: Petersen, Carl CH ([email protected])
Current Opinion in Neurobiology 2014, 26:1–6 This review comes from a themed issue on Inhibition: synapses, neurons and circuits Edited by Gordon Fishell and Ga´bor Tama´s
0959-4388/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.conb.2013.10.004
Introduction The mammalian neocortex is composed of excitatory and inhibitory neurons that interact within complex networks through electrical and chemical synapses. The excitatory neurons synaptically release the neurotransmitter glutamate onto postsynaptic targets, opening AMPA, kainate and NMDA types of ionotropic receptors permeable to cations evoking postsynaptic depolarization. The inhibitory neurons release GABA, which opens chloridepermeable GABAA receptors. Because intracellular chloride concentrations in mature neurons are typically low, the reversal potential for GABAA-evoked conductances are usually hyperpolarized relative to action potential threshold and therefore inhibitory. Although not discussed in depth in this review, it is important to note that both glutamate and GABA also activate metabotropic receptors, which contribute importantly to interneuronal signaling on slower timescales. www.sciencedirect.com
There are many more excitatory neurons than inhibitory neurons in the neocortex, with the precise numbers and ratios varying between species, cortical areas and cortical layers. This review focuses on the primary somatosensory barrel cortex, which processes sensory information related to the tactile whiskers surrounding the snout of rodents [1,2]. In total it is estimated that 11.4% (mouse) [3] or 11.6% (rat) [4] of neurons in barrel cortex are GABAergic. This ratio differs substantially comparing across the different cortical layers, with close agreement between mouse [3] and rat [4] data. The most superficial layer of the neocortex, layer 1, is composed almost exclusively of GABAergic neurons and, of course, neuropil. Layer 2 has a high density of GABAergic neurons estimated to be 16.4% (mouse) or 16.5% (rat). This contrasts with the markedly lower ratio of GABAergic neurons in layer 3 (mouse: 9.7%; rat: 9.0%) and layer 4 (mouse: 7.8%; rat: 8.1%). In deeper layers there is a high density of GABAergic neurons in layer 5 (mouse L5A: 16.5%; rat L5A: 19.7%; mouse L5B: 17.0%; rat L5B 16.2%) and a lower density in layer 6 (L6) (mouse: 9.0%; rat 8.8%). Here, in this review, we will focus specifically on the GABAergic neurons in the supragranular layers 2 and 3 (L2/3) of mouse barrel cortex, which have recently been studied in detail through combining genetics, optics and electrophysiology.
GABAergic cell-types in L2/3 mouse barrel cortex Although the GABAergic neurons only make up a small fraction of the neocortical population, they are extremely diverse in their anatomical, electrophysiological and molecular properties. Recently, it was found that three largely non-overlapping groups could account for most neocortical GABAergic neurons [5,6] (Figure 1). These three groups are molecularly defined as cells expressing the ionotropic serotonin type 3A receptor (5HT3AR), the calcium binding protein parvalbumin (PV) or the peptide somatostatin (SST). 5HT3AR-expressing GABAergic neurons
The inhibitory neurons in the superficial layers of the neocortex are dominated by a group of GABAergic neurons expressing 5HT3AR [5]. Approximately half of the GABAergic neurons in L2/3 express 5HT3AR (Figure 1b), whereas in layers 4–6 only 10% of the GABAergic neurons express 5HT3AR [5]. In the mature barrel cortex, 5HT3ARs are exclusively expressed in a subset of GABAergic neurons, which also co-express the ionotropic nicotinic acetylcholine receptor (nAChR). The 5HT3AR-expressing GABAergic neurons do not express Current Opinion in Neurobiology 2014, 26:1–6
2 Inhibition: synapses, neurons and circuits
Figure 1
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Current Opinion in Neurobiology
Three distinct genetically defined groups of neocortical GABAergic neurons. (a) Excitatory pyramidal neurons are innervated by nearby GABAergic neurons in the neocortex. The GABAergic neurons can be divided into three largely non-overlapping groups based on the expression of molecular markers. Parvalbumin-expressing (PV) GABAergic neurons preferentially innervate perisomatic regions of excitatory neurons, including axon initial segment, the soma and proximal dendrites. 5HT3AR-expressing GABAergic neurons include VIP-expressing neurons that preferentially inhibit other GABAergic neurons and neurogliaform cells that primarily release GABA non-synaptically into the extracellular space. Somatostatin-expressing (SST) GABAergic neurons preferentially innervate the distal dendrites of excitatory neurons. (b) In layers 2 and 3 of mouse barrel cortex, 50% of the GABAergic neurons express 5HT3AR; 30% express PV and 20% express SST.
PV or SST. The 5HT3AR-expressing group of GABAergic neurons comprises at least two distinct types of neocortical inhibitory neurons, one of which expresses vasoactive intestinal peptide (VIP) that preferentially innervate other GABAergic neurons [7,8] and the other type being neurogliaform cells that preferentially signal by volume transmission [9] activating metabotropic GABAB receptors [10]. Electrophysiologically, the 5HT3AR GABAergic neurons have relatively high input resistance and relatively broad action potential waveforms, firing at low frequencies. The 5HT3AR-expressing inhibitory neurons are therefore sometimes termed ‘nonfast spiking’ GABAergic neurons [11–13,14]. Developmentally, 5HT3AR GABAergic neurons are born in the caudal ganglionic eminence, whereas PV and SST neurons originate from the medial ganglionic eminence [5]. Experimental investigation of 5HT3AR GABAergic neurons is facilitated by the use of mice expressing GFP under the control of the 5HT3AR promoter [5,15]. The VIP subset of 5HT3AR-expressing neurons can be defined through mice expressing Cre-recombinase from the VIP promoter [16]. Recent evidence (discussed further below) suggests that the VIP subset of 5HT3AR-expressing neurons preferentially inhibits SST neurons, thereby disinhibiting the excitatory pyramidal neurons [17,18]. In contrast to this specific innervation of other inhibitory neurons by the VIPexpressing neurons, the other well-known subtype of 5HT3AR-expressing neurons, namely the neurogliaform cells, are thought to largely release GABA into the extrasynaptic space, thus affecting any neuronal compartment containing GABA receptors within the vicinity of the release site [9]. PV-expressing GABAergic neurons
PV-expressing neurons form about 30% of the GABAergic neurons in layer 2/3, but around 50% in layers 4–6. Electrophysiologically, PV GABAergic neurons have Current Opinion in Neurobiology 2014, 26:1–6
low input resistance, rapid membrane time-constants and very rapid action potential waveforms, being able to fire action potentials at very high rates. PV GABAergic neurons are therefore also commonly termed ‘fast-spiking’ inhibitory neurons [11–13,14,19–22]. The PV GABAergic neurons can be divided into two distinct types: basket cells, which primarily innervate proximal dendrites and perisomatic regions of the excitatory pyramidal neurons [20,22], and axo-axonic cells, which innervate the axon initial segment [23,24]. PV GABAergic neurons thus innervate electrotonically proximal regions of the excitatory neurons, where they are likely to exert a rapid and powerful inhibitory influence upon action potential initiation [13,25]. PV GABAergic neurons also receive very strong and rapid excitatory synaptic input from nearby L2/3 excitatory neurons with a high probability of finding synaptically connected pairs of neurons [13,26,27]. PV GABAergic neurons appear to sense the level of activity in surrounding nearby excitatory neurons and rapidly follow changes in overall activity levels. PV GABAergic neurons are therefore thought to play a key role in the rapid on-line millisecond-by-millisecond balancing of excitation and inhibition. Through their resonant firing properties they may also contribute to high frequency cortical rhythms, such as gamma oscillations [21]. The PV-expressing GABAergic neurons can be genetically defined through mice expressing GFP [28] or Cre-recombinase [29] from the PV gene locus. SST-expressing GABAergic neurons
The inhibitory neurons expressing SST form around 20% of the GABAergic population in L2/3, but around 40% in layers 4–6. SST neurons strongly innervate nearby excitatory neurons with high probability of finding synaptically connected pairs of neurons [30]. They typically innervate distal dendrites of excitatory neurons, and are often termed Martinotti cells [30,31]. However, in layer 4 barrel cortex, SST neurons preferentially inhibit PV www.sciencedirect.com
Cell-type specific function of cortical GABAergic neurons Petersen 3
neurons [32]. Electrophysiologically, SST neurons have a very high input resistance, and even small amounts of injected depolarizing current are sufficient to evoke action potential firing [14]. They have a rapid action potential waveform, although somewhat slower than PV neurons. SST neurons are unusual in that they receive a strongly facilitating synaptic input from nearby excitatory neurons. Whereas single action potentials in synaptically coupled excitatory neurons usually only evoke small amplitude excitatory postsynaptic potentials in SST neurons, repetitive high-frequency firing of the excitatory neuron evokes strongly facilitated neurotransmitter release, such that the repetitive firing of even just a single pyramidal neuron can drive downstream SST neurons to fire action potentials in vitro in brain slices [31], in vivo under anesthesia [33] and in vivo in awake mice [14]. SST neurons would therefore appear to integrate input over longer periods of time, being especially sensitive to bursting activity of excitatory neurons. In the mouse visual cortex, SST neurons have also been shown to integrate over large areas of cortical space, thus contributing to surround suppression [34]. As a useful experimental tool, SST neurons are labeled with GFP in GIN mice [35] and SST neurons can also be targeted through use of mice expressing Cre-recombinase from the SST gene locus [16].
Membrane potential recordings during whisker behavior Whole-cell membrane potential recordings can be made from awake, behaving head-restrained mice [36–39] and targeted through two-photon microscopy to genetically defined types of neurons expressing fluorescent proteins [11,12,14,40,41]. Membrane potential recordings provide useful information concerning the integration of synaptic inputs and their transformation into action potential output. Here, we will focus on membrane potential recordings made from the three distinct groups of GABAergic neurons in L2/3 barrel cortex of headrestrained mice during quantified whisker behavior [11,14] (Figure 2). Quiet wakefulness
During quiet wakefulness (when the whiskers are not moving) the membrane potential of excitatory, PV and 5HT3AR neurons exhibit prominent slow large-amplitude membrane potential fluctuations, which are highly synchronous within a local cortical region. On the other hand the SST neurons have less slow membrane potential fluctuations, which are anticorrelated with the other cell-types. On average during quiet wakefulness, the GABAergic neurons are about 10 mV depolarized compared to the excitatory neurons, with SST neurons being the most depolarized cell-type. Action potential threshold is similar across cell-types. Presumably because they are overall closer to threshold, the GABAergic neurons on average fire at much higher rates than www.sciencedirect.com
excitatory neurons, with both PV and SST neurons firing considerably more than 5HT3AR neurons. The 5HT3AR neurons might fire at lower frequencies on average because of strong spike-triggered currents giving rise to adapting firing patterns, unlike PV and SST neurons which can readily fire at very high frequencies without accommodation. It is also important to note that there is substantial diversity within each of the three groups of GABAergic neurons and some GABAergic neurons of each group fire at very low rates. Whisking
Mice actively move their whiskers back and forth at high frequencies (10 Hz) during exploratory behavior to scan their immediate environment. During whisking there is a prominent change in cortical state, such that the slow membrane potential fluctuations are suppressed and the cortex enters an active desynchronized state [37,38]. The change in cortical state does not depend upon sensory input from the periphery [38] and appears to be driven by increased thalamic action potential firing [42] along with input from the primary whisker motor cortex (M1) [43]. The excitatory L2/3 neurons in S1 barrel cortex depolarize slightly during whisking, but the firing rate changes little on average, because membrane potential variance is strongly decreased during whisking in the absence of the slow large-amplitude fluctuations (although some excitatory neurons increase and others decrease firing rate during whisking). The membrane potential of PV neurons does not change on average, but action potential firing is reduced during whisking, again, presumably because of the decrease in membrane potential variance during whisking. Interestingly, the 5HT3AR-expressing neurons depolarize substantially and strongly increase firing rate during whisking. In contrast, the SST neurons hyperpolarize and strongly decrease their firing rate during whisking. Whereas firing of PV and SST neurons dominates during quiet wakefulness, the active state is dominated by activity in PV and 5HT3AR neurons. The cortical state change from quiet to whisking behavior is therefore accompanied by an important reorganization of the GABAergic neuronal network activity.
Synaptic circuits driving cell-type specific activity Some of the synaptic circuits that are likely to contribute to regulating the activity of GABAergic neurons during whisking have recently been uncovered [17,18] (Figure 3). An important step was to investigate the synaptic connectivity among the different classes of GABAergic neurons. Studying the mouse visual cortex, Pfeffer et al. [17] found that the VIP subtype of 5HT3AR-expressing neurons relatively specifically inhibits SST neurons, whereas SST neurons inhibit all other types of neurons except other SST neurons and PV neurons primarily inhibit excitatory neurons and other Current Opinion in Neurobiology 2014, 26:1–6
4 Inhibition: synapses, neurons and circuits
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Current Opinion in Neurobiology
Membrane potential dynamics of GABAergic neurons during whisker behavior. (a) Overlaid images from high speed filming of the C2 whisker on the snout of a head-restrained mouse. During quiet wakefulness the whisker does not move (upper image) but during active sensing the whisker is rapidly moved back and forth at 10 Hz (lower image). (b) Membrane potential recording in L2/3 of the C2 barrel column from a non-fast spiking, putative 5HT3AR-expressing, GABAergic neuron (blue, upper traces) and from an SST neuron (brown, lower traces) during quantified whisker movements (green). During quiet wakefulness (when the whisker is not moving) the 5HT3AR neuron has slow membrane potential fluctuations and a low firing rate. During whisking the 5HT3AR neuron depolarizes and increases action potential firing. The SST neuron does not display prominent slow fluctuations, but is tonically active during quiet wakefulness. During whisking the SST neuron hyperpolarizes and reduces action potential firing. (c) The mean membrane potential during quiet wakefulness (Q) and whisking (W) quantified for excitatory (EXC) neurons and parvalbumin-expressing (PV), putative 5HT3AR-expressing (5HT) and somatostatin-expressing (SST) GABAergic neurons. (d) The mean firing rates during quiet wakefulness (Q) and whisking (W) quantified for the same cell-types. In (c) and (d), each thin line represents an individual cell and thicker lines with dots represent cell-type means along with SEM. Adapted from [11,14] with permission of Cell Press and Nature Publishing Group.
PV neurons. Similarly in L2/3 mouse barrel cortex, Lee et al. [18] found that VIP neurons strongly inhibit SST neurons, having little impact upon excitatory and PV neurons. Furthermore, Lee et al. [18] found that the VIP subtype of 5HT3AR-expressing neurons strongly increases firing rate during whisking, whereas non-VIP 5HT3AR-expressing neurons do not increase firing rate. The increased firing rate of VIP neurons appears to result, at least in part, from the substantial input that these neurons receive from M1, which is larger than the M1 input to excitatory, PV or SST neurons [18]. M1 neurons projecting to S1 might increase their firing rate during whisking and thus drive depolarization and increased firing in the VIP subtype of 5HT3AR-expressing neurons. The increased activity of VIP neurons might then inhibit Current Opinion in Neurobiology 2014, 26:1–6
the SST neurons during whisking. The SST neurons innervate distal dendrites of excitatory neurons. The reduced firing of SST neurons during whisking will thus relieve inhibition from the distal dendrites of pyramidal neurons, perhaps enhancing the integration of excitatory input arriving in L1 from M1. In support of such a hypothesis, two-photon imaging of excitatory dendrites of head-restrained mice indicates that calcium signals are prominent in L1 during whisking [14]. Such disinhibition of distal dendrites of pyramidal neurons might be an important step for sensorimotor integration during active sensing. Mechanistically, it appears that the disinhibition of distal pyramidal dendrites is mediated through reduced firing of SST neurons imposed by increased firing of VIP neurons [18]. www.sciencedirect.com
Cell-type specific function of cortical GABAergic neurons Petersen 5
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Current Opinion in Neurobiology
Circuit mechanisms driving cell-type specific activity during whisking. (a) The whisker primary motor cortex (M1) strongly innervates the primary somatosensory cortex (S1) in layer 1 and in layers 5 and 6. (b) During whisking, motor cortex input arriving in layer 1 might excite the VIP subtype of 5HT3AR-expressing GABAergic neurons, which would inhibit SST GABAergic neurons [18]. The inhibition of SST neurons during whisking would disinhibit the distal dendrites of pyramidal neurons. (c) Two-photon calcium imaging of the distal dendrites of excitatory neurons reveals prominent calcium signals during whisking, which might relate to their disinhibited state. Panel (c) is adapted from [14] with permission of the Nature Publishing Group.
cortical column form hot zones of inhibition in layers 2 and 5A. Proc Natl Acad Sci USA 2011, 108:16807-16812.
Conclusions We are just beginning to understand the neuronal connectivity and function of different types of excitatory and inhibitory neurons in L2/3 of the mouse neocortex [44]. Important advances have recently been made to genetically define different types of GABAergic neurons [16] and to record their activity during simple behaviors [14]. It is of great interest that some of the functional properties of the different types of GABAergic neurons recorded during behavior now appear to have mechanistic explanations in terms of specific synaptic connectivities among the GABAergic neurons [18]. In the future it will be important to continue to refine the genetically defined classes of GABAergic neurons, and to precisely manipulate and record their activities during increasingly sophisticated behavior.
Acknowledgements This work was funded by grants from the Swiss National Science Foundation, the Human Frontier Science Program and the European Research Council.
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ScienceDirect Cell-type specific function of GABAergic neurons in layers 2 and 3 of mouse barrel cortex Carl CH Petersen GABAergic neurons are a minor fraction of the neocortical neuronal population, but they are highly diverse in their features. The GABAergic neurons can be divided into three largely nonoverlapping groups, defined through the expression of ionotropic serotonin receptors, parvalbumin or somatostatin. Membrane potential recordings from these genetically defined GABAergic neurons in layers 2 and 3 of mouse barrel cortex reveal that they are differentially modulated by whisker behavior. As a mouse begins to explore its environment by actively moving its whiskers, motor-related signals drive different activity patterns in specific types of GABAergic neurons, thereby promoting sensorimotor integration. The neural circuit mechanisms underlying such cell-type specific activity of GABAergic neurons are now being unraveled. Addresses Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Switzerland Corresponding authors: Petersen, Carl CH ([email protected])
Current Opinion in Neurobiology 2014, 26:1–6 This review comes from a themed issue on Inhibition: synapses, neurons and circuits Edited by Gordon Fishell and Ga´bor Tama´s
0959-4388/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.conb.2013.10.004
Introduction The mammalian neocortex is composed of excitatory and inhibitory neurons that interact within complex networks through electrical and chemical synapses. The excitatory neurons synaptically release the neurotransmitter glutamate onto postsynaptic targets, opening AMPA, kainate and NMDA types of ionotropic receptors permeable to cations evoking postsynaptic depolarization. The inhibitory neurons release GABA, which opens chloridepermeable GABAA receptors. Because intracellular chloride concentrations in mature neurons are typically low, the reversal potential for GABAA-evoked conductances are usually hyperpolarized relative to action potential threshold and therefore inhibitory. Although not discussed in depth in this review, it is important to note that both glutamate and GABA also activate metabotropic receptors, which contribute importantly to interneuronal signaling on slower timescales. www.sciencedirect.com
There are many more excitatory neurons than inhibitory neurons in the neocortex, with the precise numbers and ratios varying between species, cortical areas and cortical layers. This review focuses on the primary somatosensory barrel cortex, which processes sensory information related to the tactile whiskers surrounding the snout of rodents [1,2]. In total it is estimated that 11.4% (mouse) [3] or 11.6% (rat) [4] of neurons in barrel cortex are GABAergic. This ratio differs substantially comparing across the different cortical layers, with close agreement between mouse [3] and rat [4] data. The most superficial layer of the neocortex, layer 1, is composed almost exclusively of GABAergic neurons and, of course, neuropil. Layer 2 has a high density of GABAergic neurons estimated to be 16.4% (mouse) or 16.5% (rat). This contrasts with the markedly lower ratio of GABAergic neurons in layer 3 (mouse: 9.7%; rat: 9.0%) and layer 4 (mouse: 7.8%; rat: 8.1%). In deeper layers there is a high density of GABAergic neurons in layer 5 (mouse L5A: 16.5%; rat L5A: 19.7%; mouse L5B: 17.0%; rat L5B 16.2%) and a lower density in layer 6 (L6) (mouse: 9.0%; rat 8.8%). Here, in this review, we will focus specifically on the GABAergic neurons in the supragranular layers 2 and 3 (L2/3) of mouse barrel cortex, which have recently been studied in detail through combining genetics, optics and electrophysiology.
GABAergic cell-types in L2/3 mouse barrel cortex Although the GABAergic neurons only make up a small fraction of the neocortical population, they are extremely diverse in their anatomical, electrophysiological and molecular properties. Recently, it was found that three largely non-overlapping groups could account for most neocortical GABAergic neurons [5,6] (Figure 1). These three groups are molecularly defined as cells expressing the ionotropic serotonin type 3A receptor (5HT3AR), the calcium binding protein parvalbumin (PV) or the peptide somatostatin (SST). 5HT3AR-expressing GABAergic neurons
The inhibitory neurons in the superficial layers of the neocortex are dominated by a group of GABAergic neurons expressing 5HT3AR [5]. Approximately half of the GABAergic neurons in L2/3 express 5HT3AR (Figure 1b), whereas in layers 4–6 only 10% of the GABAergic neurons express 5HT3AR [5]. In the mature barrel cortex, 5HT3ARs are exclusively expressed in a subset of GABAergic neurons, which also co-express the ionotropic nicotinic acetylcholine receptor (nAChR). The 5HT3AR-expressing GABAergic neurons do not express Current Opinion in Neurobiology 2014, 26:1–6
2 Inhibition: synapses, neurons and circuits
Figure 1
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Current Opinion in Neurobiology
Three distinct genetically defined groups of neocortical GABAergic neurons. (a) Excitatory pyramidal neurons are innervated by nearby GABAergic neurons in the neocortex. The GABAergic neurons can be divided into three largely non-overlapping groups based on the expression of molecular markers. Parvalbumin-expressing (PV) GABAergic neurons preferentially innervate perisomatic regions of excitatory neurons, including axon initial segment, the soma and proximal dendrites. 5HT3AR-expressing GABAergic neurons include VIP-expressing neurons that preferentially inhibit other GABAergic neurons and neurogliaform cells that primarily release GABA non-synaptically into the extracellular space. Somatostatin-expressing (SST) GABAergic neurons preferentially innervate the distal dendrites of excitatory neurons. (b) In layers 2 and 3 of mouse barrel cortex, 50% of the GABAergic neurons express 5HT3AR; 30% express PV and 20% express SST.
PV or SST. The 5HT3AR-expressing group of GABAergic neurons comprises at least two distinct types of neocortical inhibitory neurons, one of which expresses vasoactive intestinal peptide (VIP) that preferentially innervate other GABAergic neurons [7,8] and the other type being neurogliaform cells that preferentially signal by volume transmission [9] activating metabotropic GABAB receptors [10]. Electrophysiologically, the 5HT3AR GABAergic neurons have relatively high input resistance and relatively broad action potential waveforms, firing at low frequencies. The 5HT3AR-expressing inhibitory neurons are therefore sometimes termed ‘nonfast spiking’ GABAergic neurons [11–13,14]. Developmentally, 5HT3AR GABAergic neurons are born in the caudal ganglionic eminence, whereas PV and SST neurons originate from the medial ganglionic eminence [5]. Experimental investigation of 5HT3AR GABAergic neurons is facilitated by the use of mice expressing GFP under the control of the 5HT3AR promoter [5,15]. The VIP subset of 5HT3AR-expressing neurons can be defined through mice expressing Cre-recombinase from the VIP promoter [16]. Recent evidence (discussed further below) suggests that the VIP subset of 5HT3AR-expressing neurons preferentially inhibits SST neurons, thereby disinhibiting the excitatory pyramidal neurons [17,18]. In contrast to this specific innervation of other inhibitory neurons by the VIPexpressing neurons, the other well-known subtype of 5HT3AR-expressing neurons, namely the neurogliaform cells, are thought to largely release GABA into the extrasynaptic space, thus affecting any neuronal compartment containing GABA receptors within the vicinity of the release site [9]. PV-expressing GABAergic neurons
PV-expressing neurons form about 30% of the GABAergic neurons in layer 2/3, but around 50% in layers 4–6. Electrophysiologically, PV GABAergic neurons have Current Opinion in Neurobiology 2014, 26:1–6
low input resistance, rapid membrane time-constants and very rapid action potential waveforms, being able to fire action potentials at very high rates. PV GABAergic neurons are therefore also commonly termed ‘fast-spiking’ inhibitory neurons [11–13,14,19–22]. The PV GABAergic neurons can be divided into two distinct types: basket cells, which primarily innervate proximal dendrites and perisomatic regions of the excitatory pyramidal neurons [20,22], and axo-axonic cells, which innervate the axon initial segment [23,24]. PV GABAergic neurons thus innervate electrotonically proximal regions of the excitatory neurons, where they are likely to exert a rapid and powerful inhibitory influence upon action potential initiation [13,25]. PV GABAergic neurons also receive very strong and rapid excitatory synaptic input from nearby L2/3 excitatory neurons with a high probability of finding synaptically connected pairs of neurons [13,26,27]. PV GABAergic neurons appear to sense the level of activity in surrounding nearby excitatory neurons and rapidly follow changes in overall activity levels. PV GABAergic neurons are therefore thought to play a key role in the rapid on-line millisecond-by-millisecond balancing of excitation and inhibition. Through their resonant firing properties they may also contribute to high frequency cortical rhythms, such as gamma oscillations [21]. The PV-expressing GABAergic neurons can be genetically defined through mice expressing GFP [28] or Cre-recombinase [29] from the PV gene locus. SST-expressing GABAergic neurons
The inhibitory neurons expressing SST form around 20% of the GABAergic population in L2/3, but around 40% in layers 4–6. SST neurons strongly innervate nearby excitatory neurons with high probability of finding synaptically connected pairs of neurons [30]. They typically innervate distal dendrites of excitatory neurons, and are often termed Martinotti cells [30,31]. However, in layer 4 barrel cortex, SST neurons preferentially inhibit PV www.sciencedirect.com
Cell-type specific function of cortical GABAergic neurons Petersen 3
neurons [32]. Electrophysiologically, SST neurons have a very high input resistance, and even small amounts of injected depolarizing current are sufficient to evoke action potential firing [14]. They have a rapid action potential waveform, although somewhat slower than PV neurons. SST neurons are unusual in that they receive a strongly facilitating synaptic input from nearby excitatory neurons. Whereas single action potentials in synaptically coupled excitatory neurons usually only evoke small amplitude excitatory postsynaptic potentials in SST neurons, repetitive high-frequency firing of the excitatory neuron evokes strongly facilitated neurotransmitter release, such that the repetitive firing of even just a single pyramidal neuron can drive downstream SST neurons to fire action potentials in vitro in brain slices [31], in vivo under anesthesia [33] and in vivo in awake mice [14]. SST neurons would therefore appear to integrate input over longer periods of time, being especially sensitive to bursting activity of excitatory neurons. In the mouse visual cortex, SST neurons have also been shown to integrate over large areas of cortical space, thus contributing to surround suppression [34]. As a useful experimental tool, SST neurons are labeled with GFP in GIN mice [35] and SST neurons can also be targeted through use of mice expressing Cre-recombinase from the SST gene locus [16].
Membrane potential recordings during whisker behavior Whole-cell membrane potential recordings can be made from awake, behaving head-restrained mice [36–39] and targeted through two-photon microscopy to genetically defined types of neurons expressing fluorescent proteins [11,12,14,40,41]. Membrane potential recordings provide useful information concerning the integration of synaptic inputs and their transformation into action potential output. Here, we will focus on membrane potential recordings made from the three distinct groups of GABAergic neurons in L2/3 barrel cortex of headrestrained mice during quantified whisker behavior [11,14] (Figure 2). Quiet wakefulness
During quiet wakefulness (when the whiskers are not moving) the membrane potential of excitatory, PV and 5HT3AR neurons exhibit prominent slow large-amplitude membrane potential fluctuations, which are highly synchronous within a local cortical region. On the other hand the SST neurons have less slow membrane potential fluctuations, which are anticorrelated with the other cell-types. On average during quiet wakefulness, the GABAergic neurons are about 10 mV depolarized compared to the excitatory neurons, with SST neurons being the most depolarized cell-type. Action potential threshold is similar across cell-types. Presumably because they are overall closer to threshold, the GABAergic neurons on average fire at much higher rates than www.sciencedirect.com
excitatory neurons, with both PV and SST neurons firing considerably more than 5HT3AR neurons. The 5HT3AR neurons might fire at lower frequencies on average because of strong spike-triggered currents giving rise to adapting firing patterns, unlike PV and SST neurons which can readily fire at very high frequencies without accommodation. It is also important to note that there is substantial diversity within each of the three groups of GABAergic neurons and some GABAergic neurons of each group fire at very low rates. Whisking
Mice actively move their whiskers back and forth at high frequencies (10 Hz) during exploratory behavior to scan their immediate environment. During whisking there is a prominent change in cortical state, such that the slow membrane potential fluctuations are suppressed and the cortex enters an active desynchronized state [37,38]. The change in cortical state does not depend upon sensory input from the periphery [38] and appears to be driven by increased thalamic action potential firing [42] along with input from the primary whisker motor cortex (M1) [43]. The excitatory L2/3 neurons in S1 barrel cortex depolarize slightly during whisking, but the firing rate changes little on average, because membrane potential variance is strongly decreased during whisking in the absence of the slow large-amplitude fluctuations (although some excitatory neurons increase and others decrease firing rate during whisking). The membrane potential of PV neurons does not change on average, but action potential firing is reduced during whisking, again, presumably because of the decrease in membrane potential variance during whisking. Interestingly, the 5HT3AR-expressing neurons depolarize substantially and strongly increase firing rate during whisking. In contrast, the SST neurons hyperpolarize and strongly decrease their firing rate during whisking. Whereas firing of PV and SST neurons dominates during quiet wakefulness, the active state is dominated by activity in PV and 5HT3AR neurons. The cortical state change from quiet to whisking behavior is therefore accompanied by an important reorganization of the GABAergic neuronal network activity.
Synaptic circuits driving cell-type specific activity Some of the synaptic circuits that are likely to contribute to regulating the activity of GABAergic neurons during whisking have recently been uncovered [17,18] (Figure 3). An important step was to investigate the synaptic connectivity among the different classes of GABAergic neurons. Studying the mouse visual cortex, Pfeffer et al. [17] found that the VIP subtype of 5HT3AR-expressing neurons relatively specifically inhibits SST neurons, whereas SST neurons inhibit all other types of neurons except other SST neurons and PV neurons primarily inhibit excitatory neurons and other Current Opinion in Neurobiology 2014, 26:1–6
4 Inhibition: synapses, neurons and circuits
Figure 2
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Current Opinion in Neurobiology
Membrane potential dynamics of GABAergic neurons during whisker behavior. (a) Overlaid images from high speed filming of the C2 whisker on the snout of a head-restrained mouse. During quiet wakefulness the whisker does not move (upper image) but during active sensing the whisker is rapidly moved back and forth at 10 Hz (lower image). (b) Membrane potential recording in L2/3 of the C2 barrel column from a non-fast spiking, putative 5HT3AR-expressing, GABAergic neuron (blue, upper traces) and from an SST neuron (brown, lower traces) during quantified whisker movements (green). During quiet wakefulness (when the whisker is not moving) the 5HT3AR neuron has slow membrane potential fluctuations and a low firing rate. During whisking the 5HT3AR neuron depolarizes and increases action potential firing. The SST neuron does not display prominent slow fluctuations, but is tonically active during quiet wakefulness. During whisking the SST neuron hyperpolarizes and reduces action potential firing. (c) The mean membrane potential during quiet wakefulness (Q) and whisking (W) quantified for excitatory (EXC) neurons and parvalbumin-expressing (PV), putative 5HT3AR-expressing (5HT) and somatostatin-expressing (SST) GABAergic neurons. (d) The mean firing rates during quiet wakefulness (Q) and whisking (W) quantified for the same cell-types. In (c) and (d), each thin line represents an individual cell and thicker lines with dots represent cell-type means along with SEM. Adapted from [11,14] with permission of Cell Press and Nature Publishing Group.
PV neurons. Similarly in L2/3 mouse barrel cortex, Lee et al. [18] found that VIP neurons strongly inhibit SST neurons, having little impact upon excitatory and PV neurons. Furthermore, Lee et al. [18] found that the VIP subtype of 5HT3AR-expressing neurons strongly increases firing rate during whisking, whereas non-VIP 5HT3AR-expressing neurons do not increase firing rate. The increased firing rate of VIP neurons appears to result, at least in part, from the substantial input that these neurons receive from M1, which is larger than the M1 input to excitatory, PV or SST neurons [18]. M1 neurons projecting to S1 might increase their firing rate during whisking and thus drive depolarization and increased firing in the VIP subtype of 5HT3AR-expressing neurons. The increased activity of VIP neurons might then inhibit Current Opinion in Neurobiology 2014, 26:1–6
the SST neurons during whisking. The SST neurons innervate distal dendrites of excitatory neurons. The reduced firing of SST neurons during whisking will thus relieve inhibition from the distal dendrites of pyramidal neurons, perhaps enhancing the integration of excitatory input arriving in L1 from M1. In support of such a hypothesis, two-photon imaging of excitatory dendrites of head-restrained mice indicates that calcium signals are prominent in L1 during whisking [14]. Such disinhibition of distal dendrites of pyramidal neurons might be an important step for sensorimotor integration during active sensing. Mechanistically, it appears that the disinhibition of distal pyramidal dendrites is mediated through reduced firing of SST neurons imposed by increased firing of VIP neurons [18]. www.sciencedirect.com
Cell-type specific function of cortical GABAergic neurons Petersen 5
Figure 3
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Current Opinion in Neurobiology
Circuit mechanisms driving cell-type specific activity during whisking. (a) The whisker primary motor cortex (M1) strongly innervates the primary somatosensory cortex (S1) in layer 1 and in layers 5 and 6. (b) During whisking, motor cortex input arriving in layer 1 might excite the VIP subtype of 5HT3AR-expressing GABAergic neurons, which would inhibit SST GABAergic neurons [18]. The inhibition of SST neurons during whisking would disinhibit the distal dendrites of pyramidal neurons. (c) Two-photon calcium imaging of the distal dendrites of excitatory neurons reveals prominent calcium signals during whisking, which might relate to their disinhibited state. Panel (c) is adapted from [14] with permission of the Nature Publishing Group.
cortical column form hot zones of inhibition in layers 2 and 5A. Proc Natl Acad Sci USA 2011, 108:16807-16812.
Conclusions We are just beginning to understand the neuronal connectivity and function of different types of excitatory and inhibitory neurons in L2/3 of the mouse neocortex [44]. Important advances have recently been made to genetically define different types of GABAergic neurons [16] and to record their activity during simple behaviors [14]. It is of great interest that some of the functional properties of the different types of GABAergic neurons recorded during behavior now appear to have mechanistic explanations in terms of specific synaptic connectivities among the GABAergic neurons [18]. In the future it will be important to continue to refine the genetically defined classes of GABAergic neurons, and to precisely manipulate and record their activities during increasingly sophisticated behavior.
Acknowledgements This work was funded by grants from the Swiss National Science Foundation, the Human Frontier Science Program and the European Research Council.
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