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Untangling GABAergic wiring in the cortical microcircuit
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ScienceDirect Untangling GABAergic wiring in the cortical microcircuit Yoshiyuki Kubota1,2,3 The cerebral cortical microcircuit is composed of pyramidal and non-pyramidal cells and subcortical and cortico-cortical afferents. These constitute a complex wiring structure that remains poorly understood. At least ten non-pyramidal cell subtypes are known. These innervate different target neuronal domains, and have a key role in regulating cortical neuronal activity. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cerebral cortex, and most cortical inhibitory synapses originate from non-pyramidal cells. Therefore, investigating the morphological and functional wiring properties of GABAergic non-pyramidal cells is critical to understanding the functional architecture of the cortical microcircuitry. This review focuses on current understanding of the different roles of inhibitory GABAergic non-pyramidal cell subtypes in cortical functions. Addresses 1 Division of Cerebral Circuitry, National Institute for Physiological Sciences, Okazaki, Japan 2 Department of Physiological Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan 3 Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan Corresponding author: Kubota, Yoshiyuki ([email protected])
Current Opinion in Neurobiology 2014, 26:7–14 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.2013.10.003
Introduction The cortical microcircuit is important for information processing in cognition, emotion, memory, motor control, sensory perception, and other functions. However, the functional architecture and mechanistic principles of the microcircuit are poorly understood. Both the functional significance of the neuronal components of the microcircuit, and the wiring principles operating between them, remain to be clarified. Inhibitory synapses constitute approximately 20% of all synapses in the cortical microcircuit, and regulate pyramidal cell activity. Perturbation of inhibitory circuit function is associated with disorders including autism [1,2], epilepsy [3], and schizophrenia [4–6]. Most cortical inhibitory synapses originate from cortical non-pyramidal cells, of which at least ten subtypes are found in the cortex [7,8,9]. Each non-pyramidal cell www.sciencedirect.com
subtype innervates distinct target domains within different cortical neuronal subgroups [10,11,12,13,14,15,16]. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cerebral cortex, and most cortical inhibitory synapses originate from non-pyramidal cells [7,10,17,18,19,20]. This review summarizes the latest research findings concerning inhibitory GABAergic nonpyramidal cells, and explores their roles in the functional architecture of the cortical microcircuit.
Non-pyramidal cell subtypes Cortical microcircuitry is composed of pyramidal cells, non-pyramidal cells, and afferent neurons from the thalamus and other subcortical regions. These cell types are arranged in a well-ordered wiring pattern and establish the complex functional architecture of the microcircuit. A wide variety of neuronal subtypes are found in the neocortex. In particular, many different non-pyramidal cell subtypes exist, although they account for only 20% of all cortical neurons. Non-pyramidal cell subtypes are morphologically classified into basket cells, chandelier cells, Martinotti cells, double bouquet cells, neurogliaform cells, and others (Figure 1), according to their distinct axonal and dendritic arborization patterns [21,22,23]. Their morphological differences suggest that different non-pyramidal cell subtypes innervate different domains of target neurons, and this is indeed the case [10,14] (Figure 2). Distinct patterns of neurochemical marker expression such as parvalbumin (PV), calretinin (CR), somatostatin (SOM), vasoactive intestinal polypeptide (VIP) and different firing properties are also observed in cortical non-pyramidal cell subtypes (Figure 1) [7,9,24,25,26]. Morphologically distinct non-pyramidal cell subtypes possess certain combinations of markers and firing properties [7,24,26,27], and are active with specific timing during different states [28]. This suggests that each non-pyramidal cell subtype has a distinct role in the cortical microcircuit. The characteristics of the most prevalent GABAergic non-pyramidal subtypes are described below.
Target domains of non-pyramidal cells Non-pyramidal cells innervate three different target domains, soma, dendritic shaft, and dendrite spines, in different animal species including humans [12–15]. The functional significance of these three inhibition modalities is likely to be different. The somatic synapses may provide strong global control of pyramidal cell activity. IPSPs by dendritic shaft synapses are unlikely to conduct over long distances, effectively reducing only adjacent EPSPs [29]. They intercept local dendritic excitatory postsynaptic potentials and control integration of these Current Opinion in Neurobiology 2014, 26:7–14
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Figure 1 RS Martinotti SOM+
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Current Opinion in Neurobiology
Subtypes of cortical non-pyramidal cells. Upper panels show drawings of different subtypes of cortical non-pyramidal cells in different layers. Cell soma and dendrites are shown in black and axonal fibers are shown in red. Lower panels show examples of firing patterns after step-current injection into cortical non-pyramidal cell subtypes. FS, fast spiking; LS, late spiking; RS, regular spiking; SOM, somatostatin; AAc, alpha-actinin-2; CR, calretinin; CRF, corticotropin-releasing factor; VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin. Current Opinion in Neurobiology 2014, 26:7–14
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Untangling GABAergic wiring Kubota 9
Figure 2
elongated neurogliaform
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Summary diagram showing the cortical microcircuit. Inhibitory non-pyramidal cell subtypes innervate different domains of layer 5 pyramidal cells and other non-pyramidal cells. The thalamo-cortical fibers innervate spines contacted by inhibitory boutons. The other excitatory axon terminals are not shown. FS, fast spiking; RS/BS, regular/burst spiking; LS, late spiking; SOM, somatostatin; AAc, alpha-actinin-2; CR, calretinin; CRF, corticotropinreleasing factor; VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin; PV, parvalbumin; VVA, vicia villosa agglutinin; NPY, neuropeptide Y; NOS, nitric oxide synthase; SPR, substance P receptor.
potentials from more distal dendrites [30]. By contrast, synapses on spines have strictly local actions to veto excitatory inputs to that spine [31], and are known as thalamo-cortical excitatory efferents [14]. Thus, inhibitory synapses made at these three sites provide different forms of control over excitatory signals transmitted to pyramidal cells. Interestingly, among these three target domains, inhibitory dendritic spine synapses and their recipient spines are highly plastic, depending on the visual experience [32] and whisker stimulation [33].
layer 5 (L5) pyramidal neurons [10]. Basket cell axons primarily target the somata and proximal dendrites, while Martinotti cells target the apical tuft dendrites. Similarly, double-bouquet cells provide inhibition to the middle and distal basal dendrites, neurogliaform cells target secondary and tertiary tuft dendrites, and chandelier cells selectively inhibit axonal initial segments, and so on. However, these non-pyramidal cell subtypes may innervate other subdomains of other classes of target neuron [10,11].
Basket cells Many non-pyramidal cell subtypes selectively inhibit specific subcellular domains on target neurons. For instance, a variety of non-pyramidal neuron subtypes selectively inhibit nonoverlapping subcellular compartments of www.sciencedirect.com
Relative to other non-pyramidal neuron subtypes, basket cells preferentially innervate the somata of pyramidal neurons. In the rat cortex, >14% of basket neuron boutons arrive at somata [9,22]. On the other hand, Current Opinion in Neurobiology 2014, 26:7–14
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non-basket cells typically provide only few inputs onto somata (0–7%) [9,22]. PV-positive cells constitute one of the major non-pyramidal cell subtypes, and are mostly fast-spiking (FS) interneurons. PV-expressing cells mainly inhibit both pyramidal cells and PV-positive cells [19]. FS basket cells are the largest cell population among the PV-positive cells, and represent 40–50% of non-pyramidal cells [9,25,26,34,35]. Their axon fibers extend horizontally in a layer-specific manner from the soma, so called nest basket cell [36]. A few descending axon collaterals are extended, but these rarely innervate layer 1 (L1). Around 25% of the axon terminals of FS basket cells innervate cell soma [22]; other axon terminals innervate the dendrites and spine heads of target neurons [14]. The somatic inhibition effectively decreases the target cell activity. This pattern of innervation is similar to other cortical inhibitory interneurons, although not all subtypes innervate cell soma [14]. The FS basket cells of the rat cortex have 3000–5000 axonal boutons [22]. Each FS basket cell innervates target pyramidal cells with 5–15 terminal boutons, and is therefore estimated to innervate 200–1000 pyramidal cells. FS basket cells can fire repetitively at up to 400 Hz [37] because K+ channels containing Kv3.1 and Kv3.2 proteins allow sustained high-frequency firing [38–40]. However, functionally powerful autapses provide feedback inhibition that reduces excitability [41]. In in vivo conditions, FS basket cells fire repetitively at up to 30–50 Hz in the motor cortex during motor behavior [42], at up to 30 Hz in the prefrontal cortex during tail pinch [43], and at 20– 30 Hz in the hippocampus [44]. They also discharge rhythmically with spindle (7–14 Hz) and gamma (30– 80 Hz) oscillations [45], so firing frequency is well controlled in vivo. About 80% of PV-positive cells, mostly FS basket cells, express connexin 36 [46], which forms an electrical synapse using gap junctions to connect with other FS basket cells, with a coupling coefficient of around 0.02 [47–49]. Each PV-positive cell has around 60 gap junctions [50]. Synchronization of FS basket cell activity through the electrical coupling via gap junctions will reinforce the population inhibition in the cortical microcircuit. Non-FS basket cell subtype population expresses CR, cholecystokinin (CCK), VIP, and/or corticotropin-releasing factor (CRF) and show regular or burst spiking (RS/ BS) patterns [11]. They are subdivided into three groups, large basket cells, which express CCK only, small basket or descending basket cells [22,36]. Thirty-seven percent of CR/VIP/CCK-positive basket cells also express connexin 36 [46], and therefore may connect with each other through electrical synapses. Large basket cells have 2000–4000 axonal boutons, while small basket cells have 1000–2500 boutons [22]; therefore, they may innervate 100–500 neurons. RS/BS CCK-positive cells may also express the cannabinoid receptor (CB1R) [51,52], resulting in a difference in activity compared with FS basket Current Opinion in Neurobiology 2014, 26:7–14
cells. On subtle and repetitive excitation, CB1R-positive basket cells respond late and do not show repetitive response, while FS basket cells respond immediately and repetitively [53,54]. CCK-expressing basket cells also release GABA more asynchronously than FS basket cells [55]. Two different basket cell subtypes respond complimentary to the repetitive signals. It suggests that they have different functional roles in cortical microcircuit architecture [56]. Basket cells with late spiking (LS) properties are also found in the cortex [22]. Their axons and dendrites branch less frequently than those of the other basket cells, and are sparsely distributed in their dendritic and axonal fields (Figure 1).
Martinotti and related cells The second largest non-pyramidal cell subtype is SOMpositive cells, which comprise 20–30% of the non-pyramidal cell population [9,25,26,34,35]. They show low threshold spike or RS/BS firing patterns, and express neuropeptide Y (NPY), nitric oxide synthase (NOS), substance P receptor (SPR), and/or calbindin D28k [9,25,26,34,35], in addition to SOM. Most are Martinotti cells, which display ascending axonal arborization to L1, with SOM/NPY/calbindin D28k expression. They mainly innervate the apical and tuft dendrites of pyramidal cells [10,57,58]. Martinotti cells inhibit calcium spikes in L5 tuft dendrites [59] and also inhibit all other interneurons [19]. Approximately 10–25% of SOM-positive cells and 15–45% of NPY-positive cells also express both NOS and SPR [25,26,60]. This subtype showing SOM/NPY/ NOS/SPR expression loses spines during development [26] and known to extend long projecting axons to other cortical areas [18,61], those characteristics differs from the Martinotti cells, which have many spines on their dendrites and ascending axons to L1. Around half of all SOMpositive cells express connexin 36 [46] and are electrically coupled to cells of a similar subtype to enhance synchronized activity [48].
Double bouquet and related cells The third major non-pyramidal cell subtype are double bouquet cells and related cells, which have descending axonal fibers. They constitute 15–35% of the non-pyramidal cell population of the cortical microcircuit [9,25,26,34,35]. They show RS/BS properties and express VIP, CRF, CR, serotonin 5-hydroxytryptamine 3A receptor (5-HT3A), or CCK [25,26,62]. Co-express patterns of those neurochemical markers depend on the layers. For instance, about 60% of this subtype cells express both CRF and VIP, 40% cells express only CR, and all express 5-HT3A in L2/3. CR-positive interneurons in the rat hippocampus innervate other interneurons [63]. In the primary somatosensory cortex (S1), VIP/5-HT3Apositive double bouquet cells receive excitatory signals from the primary motor cortex (M1) and in turn innervate www.sciencedirect.com
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mainly SOM-positive Martinotti cells and L5 pyramidal cells. The SOM-positive inhibitory cells then innervate the L5 pyramidal cells. VIP/5-HT3A-positive cells and SOM-positive cells also innervate PV-positive FS basket cells, which are driven by excitatory signals from M1 and innervate the pyramidal cells with feedforward inhibition (personal communication from Dr. SooHyun Lee) [19,62,64]. This subtype is primarily responsible for the control of other non-pyramidal cells.
Neurogliaform and related cells Neurogliaform cells express alpha-actinin-2 (AAc) and NPY, weakly express NOS, and exhibit LS membrane properties [9,26,60,65]. NPY-expressing neurons in layers 2/3–6 co-express either AAc or SOM but not both [9]. Therefore, NPY-positive cells are classified into neurogliaform (i.e., AAc-containing), Martinotti (i.e., SOM-containing) or NOS cell (i.e., NOS-containing and SOM-containing). They have more primary dendrites and more frequent branching points, and consequently a smaller dendritic field, than other non-pyramidal cell subtypes [23]. This subtype has the longest axon length (about 30 mm) of the non-pyramidal cells, and short interbouton intervals. This results in high bouton density in the axonal field. Neurogliaform cells are a possible source of slow inhibition due to their action on metabotropic GABAB receptors [66]. Two related cell subgroups are found in L1. AAc-only cells resemble neurogliaform cells, with extensive local axon ramification and a large number of primary dendrites with frequent branching, but axons are extended horizontally among L1. They are therefore known as elongated neurogliaform cells, and most show LS nonadapting firing properties [10,26]. The other L1 subgroups are AAc/CR-positive cells resembling LS basket cells, with sparsely distributed axons, descending axonal arbors, and horizontally extended dendrites. These are called single-bouquet cells, and they mostly show adapting non-LS firing properties [10,26]. In rats, these L1 interneurons are excited by callosal excitatory axonal fibers after ipsilateral hindlimb stimulation, and inhibit spiking activity of L5 pyramidal cell with GABABmediated inhibition in vivo [67]. They exert functionally different properties to inhibit L5 pyramidal cells [56]. The single-bouquet cells disinhibit L5 pyramidal cells via L2/3 interneurons, and the elongated neurogliaform cells inhibit both L5 pyramidal cell and L2/3 interneuron and functionally this inhibitory connections reduce the dendritic complex spike generation in L5 pyramidal cells (Figure 2) [10].
Chandelier cells FS chandelier cells, a minor FS cell population that express PV, almost exclusively innervate the initial segments of pyramidal cell axons, with vertically oriented axon-terminal bouton alignment [11,68]. Chandelier cells www.sciencedirect.com
fire at the troughs of pyramidal cell discharges, slightly faster than basket cell discharges, during theta rhythm generation in the hippocampus [28]. FS chandelier cells are believed to inhibit pyramidal cell activity by releasing the inhibitory neurotransmitter GABA; this should have a hyperpolarizing or shunting postsynaptic effect on the target pyramidal cell and efficiently suppress the target cell activity [69]. However, chandelier cells may excite postsynaptic pyramidal cells under certain conditions due to the nature of the membrane of the axon initial segment of the target pyramidal cell, which has a low potassium chloride co-transporter 2 (KCC2) distribution [70]. This may induce an influx of chloride ions ([Cl ]in) into the cytosol of the axon initial segment, which leads to the depolarizing effects of GABA [71,72]. However, this result is inconsistent with the population activity timing of pyramidal and chandelier cells during theta rhythm oscillation, in which chandelier cells discharge during the trough of pyramidal cell discharges [28], and with a local unitary field analysis of spike discharge of axo-axonic cells in the hippocampus [73]. Target pyramidal cell inhibition or excitation appears to depend on the postsynaptic membrane potential, which may vary under different conditions [74]. Chandelier cells are electrically coupled with each other, with a coupling coefficient of about 0.05 [74,75]. This suggests chandelier cells discharge synchronously to reduce the target pyramidal cell population activity effectively. Chandelier cells without FS firing properties/PV expression are also found, and these cells express CRF [65,75,76].
Connection selectivity PV-positive FS basket cells and SOM-positive Martinotti cells non-selectively innervate surrounding pyramidal cells [77,78] and are not involved in the fine-scale network of the cortical microcircuit [79]. In primary visual cortex, unlike excitatory pyramidal cells, non-pyramidal cells do not show orientation tuning [80,81]. However their dendrites show pronounced orientation tuned domains, individual dendritic branches often have multiple domains with distinct preferred orientations [82], which receive convergent input from nearby pyramidal cells with a broad range of preferred orientations [83]. These results indicate that, unlike excitatory pyramidal cells, non-pyramidal cells are not involved in connection selectivity of functional cortical microcircuitry [84,85].
Concluding remarks Cortical GABAergic non-pyramidal cells are heterogeneous in terms of dendritic and axonal morphology, synaptic connections, physiological properties, and neurochemical expression. Each subtype is likely to have a different functional role in regulating cortical microcircuit activity. Most non-pyramidal cell subtypes have been identified based on morphological, neurochemical, and physiological differences. It will be of great interest to Current Opinion in Neurobiology 2014, 26:7–14
12 Inhibition: Synapses, Neurons and Circuits
further investigate their functional as well as anatomical synaptic wiring in the cortical microcircuit.
Acknowledgements We thank Drs. Yasuo Kawaguchi and Fuyuki Karube for Neurolucida neuron drawings and Dr. Allan T Gulledge for comments. This work was supported by JSPS KAKENHI (Grant numbers 24120718 and 25290012) from the MEXT of Japan.
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39. Erisir A, Lau D, Rudy B, Leonard CS: Function of specific k(+) channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J Neurophysiol 1999, 82:2476-2489. 40. Massengill JL, Smith MA, Son DI, O’Dowd DK: Differential expression of k4-ap currents and kv3.1 potassium channel transcripts in cortical neurons that develop distinct firing phenotypes. J Neurosci Official J Soc Neurosci 1997, 17:31363147. 41. Bacci A, Huguenard JR, Prince DA: Functional autaptic neurotransmission in fast-spiking interneurons: a novel form of feedback inhibition in the neocortex. J Neurosci 2003, 23:859-866. 42. Isomura Y, Harukuni R, Takekawa T, Aizawa H, Fukai T: Microcircuitry coordination of cortical motor information in self-initiation of voluntary movements. Nat Neurosci 2009, 12:1586-1593. 43. Massi L, Lagler M, Hartwich K, Borhegyi Z, Somogyi P, Klausberger T: Temporal dynamics of parvalbumin-expressing axo-axonic and basket cells in the rat medial prefrontal cortex in vivo. J Neurosci Official J Soc Neurosci 2012, 32:16496-16502. The distinct firing dynamics and synaptic targets of axo-axonic and PVexpressing cells were analyzed in the prefrontal networks. 44. Lapray D, Lasztoczi B, Lagler M, Viney TJ, Katona L, Valenti O, Hartwich K, Borhegyi Z, Somogyi P, Klausberger T: Behaviordependent specialization of identified hippocampal interneurons. Nat Neurosci 2012, 15:1265-1271. Spike-timing dynamics of hippocampal PV-expressing basket cells and NOS/NPY-expressing ivy cells were analyzed in drug-free, freely moving rats. The basket cells coordinate cell assemblies in a behavioral statecontingent manner, whereas persistently firing ivy cells may control network excitability and homeostasis. www.sciencedirect.com
55. Hefft S, Jonas P: Asynchronous GABA release generates longlasting inhibition at a hippocampal interneuron-principal neuron synapse. Nat Neurosci 2005, 8:1319-1328. 56. Larkum ME: The yin and yang of cortical layer 1. Nat Neurosci 2013, 16:114-115. 57. Kapfer C, Glickfeld LL, Atallah BV, Scanziani M: Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex. Nat Neurosci 2007, 10:743-753. 58. Silberberg G, Markram H: Disynaptic inhibition between neocortical pyramidal cells mediated by martinotti cells. Neuron 2007, 53:735-746. 59. Murayama M, Perez-Garci E, Nevian T, Bock T, Senn W, Larkum ME: Dendritic encoding of sensory stimuli controlled by deep cortical interneurons. Nature 2009, 457:1137-1141. 60. Karagiannis A, Gallopin T, David C, Battaglia D, Geoffroy H, Rossier J, Hillman EM, Staiger JF, Cauli B: Classification of NPYexpressing neocortical interneurons. J Neurosci Official J Soc Neurosci 2009, 29:3642-3659. 61. Tomioka R, Rockland KS: Long-distance corticocortical GABAergic neurons in the adult monkey white and gray matter. J Comp Neurol 2007, 505:526-538. 62. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B: The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci Official J Soc Neurosci 2010, 30:16796-16808. 63. Gulyas AI, Hajos N, Freund TF: Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J Neurosci Official J Soc Neurosci 1996, 16:3397-3411. Current Opinion in Neurobiology 2014, 26:7–14
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64. Hioki H, Okamoto S, Konno M, Kameda H, Sohn J, Kuramoto E, Fujiyama F, Kaneko T: Cell type-specific inhibitory inputs to dendritic and somatic compartments of parvalbuminexpressing neocortical interneuron. J Neurosci Official J Soc Neurosci 2013, 33:544-555. The inhibitory synaptic inputs of GFP-labeled PV-positive neurons in the mouse somatosensory cortex were quantitatively analyzed. PV-positive neurons receive somatic inputs from VIP-positive neurons as well as dendritic inputs from SOM-positive cells and PV-positive cells. 65. Kawaguchi Y: Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J Neurosci Official J Soc Neurosci 1995, 15:2638-2655. 66. Tamas G, Lorincz A, Simon A, Szabadics J: Identified sources and targets of slow inhibition in the neocortex. Science 2003, 299:1902-1905. 67. Palmer LM, Schulz JM, Murphy SC, Ledergerber D, Murayama M, Larkum ME: The cellular basis of GABA(b)-mediated interhemispheric inhibition. Science 2012, 335:989-993. The firing of L5 pyramidal neurons in rat somatosensory cortex induced by contralateral sensory stimulation was inhibited due to direct inhibition of apical dendrites via layer 1 interneurons mediated by GABAB receptors. 68. Somogyi P: A specific ‘axo-axonal’ interneuron in the visual cortex of the rat. Brain Res 1977, 136:345-350. 69. Hao J, Wang XD, Dan Y, Poo MM, Zhang XH: An arithmetic rule for spatial summation of excitatory and inhibitory inputs in pyramidal neurons. Proc Natl Acad Sci USA 2009, 106:21906-21911. 70. Baldi R, Varga C, Tamas G: Differential distribution of kcc2 along the axo-somato-dendritic axis of hippocampal principal cells. Eur J Neurosci 2010, 32:1319-1325. 71. Szabadics J, Varga C, Molnar G, Olah S, Barzo P, Tamas G: Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 2006, 311:233-235. 72. Woodruff A, Xu Q, Anderson SA, Yuste R: Depolarizing effect of neocortical chandelier neurons. Front Neural Circuits 2009, 3:15. 73. Glickfeld LL, Roberts JD, Somogyi P, Scanziani M: Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis. Nat Neurosci 2009, 12:21-23. 74. Woodruff AR, McGarry LM, Vogels TP, Inan M, Anderson SA, Yuste R: State-dependent function of neocortical chandelier cells. J Neurosci Official J Soc Neurosci 2011, 31:17872-17886. Chandelier cells were observed to have excitatory or inhibitory influences on target pyramidal cells. They appear to play a dual role depending on the circuit condition. 75. Taniguchi H, Lu J, Huang ZJ: The spatial and temporal origin of chandelier cells in mouse neocortex. Science 2013, 339:70-74.
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Chandelier cells were analyzed in terms of their developmental trajectory and were found to derive from the ventral germinal zone of the lateral ventricle during late gestation and require Nkx2.1. 76. Lewis DA, Lund JS: Heterogeneity of chandelier neurons in monkey neocortex: corticotropin-releasing factor- and parvalbumin-immunoreactive populations. J Comp Neurol 1990, 293:599-615. 77. Fino E, Yuste R: Dense inhibitory connectivity in neocortex. Neuron 2011, 69:1188-1203. SOM-positive GABAergic interneurons were found to connect with surrounding pyramidal cells without preference. Local inhibitory connectivity is promiscuous and does not form subnetworks. 78. Packer AM, Yuste R: Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition? J Neurosci Official J Soc Neurosci 2011, 31:13260-13271. PV-positive GABAergic interneurons were found to connect with surrounding pyramidal cells without preference. Local inhibitory connectivity is promiscuous and does not form subnetworks. 79. Yoshimura Y, Callaway EM: Fine-scale specificity of cortical networks depends on inhibitory cell type and connectivity. Nat Neurosci 2005, 8:1552-1559. 80. Kerlin AM, Andermann ML, Berezovskii VK, Reid RC: Broadly tuned response properties of diverse inhibitory neuron subtypes in mouse visual cortex. Neuron 2010, 67:858-871. 81. Sohya K, Kameyama K, Yanagawa Y, Obata K, Tsumoto T: GABAergic neurons are less selective to stimulus orientation than excitatory neurons in layer II/III of visual cortex, as revealed by in vivo functional Ca2+ imaging in transgenic mice. J Neurosci Official J Soc Neurosci 2007, 27:2145-2149. 82. Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, Schreiter ER, Kerr RA, Orger MB, Jayaraman V, Looger LL: Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 2013, 499:295-300. Ultrasensitive protein calcium sensors (GCaMP6) were developed and used to show that spine calcium changes during orientation tuning can be clearly identified in vivo. Using this calcium sensor, the orientation tuned dendritic domains were clearly identified in the non-pyramidal cells of primary visual cortex. 83. Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, Reid RC: Network anatomy and in vivo physiology of visual cortical neurons. Nature 2011, 471:177-182. 84. Ohki K, Chung S, Ch’ng YH, Kara P, Reid RC: Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex. Nature 2005, 433:597-603. 85. Yoshimura Y, Dantzker JL, Callaway EM: Excitatory cortical neurons form fine-scale functional networks. Nature 2005, 433:868-873.
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ScienceDirect Untangling GABAergic wiring in the cortical microcircuit Yoshiyuki Kubota1,2,3 The cerebral cortical microcircuit is composed of pyramidal and non-pyramidal cells and subcortical and cortico-cortical afferents. These constitute a complex wiring structure that remains poorly understood. At least ten non-pyramidal cell subtypes are known. These innervate different target neuronal domains, and have a key role in regulating cortical neuronal activity. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cerebral cortex, and most cortical inhibitory synapses originate from non-pyramidal cells. Therefore, investigating the morphological and functional wiring properties of GABAergic non-pyramidal cells is critical to understanding the functional architecture of the cortical microcircuitry. This review focuses on current understanding of the different roles of inhibitory GABAergic non-pyramidal cell subtypes in cortical functions. Addresses 1 Division of Cerebral Circuitry, National Institute for Physiological Sciences, Okazaki, Japan 2 Department of Physiological Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan 3 Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan Corresponding author: Kubota, Yoshiyuki ([email protected])
Current Opinion in Neurobiology 2014, 26:7–14 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.2013.10.003
Introduction The cortical microcircuit is important for information processing in cognition, emotion, memory, motor control, sensory perception, and other functions. However, the functional architecture and mechanistic principles of the microcircuit are poorly understood. Both the functional significance of the neuronal components of the microcircuit, and the wiring principles operating between them, remain to be clarified. Inhibitory synapses constitute approximately 20% of all synapses in the cortical microcircuit, and regulate pyramidal cell activity. Perturbation of inhibitory circuit function is associated with disorders including autism [1,2], epilepsy [3], and schizophrenia [4–6]. Most cortical inhibitory synapses originate from cortical non-pyramidal cells, of which at least ten subtypes are found in the cortex [7,8,9]. Each non-pyramidal cell www.sciencedirect.com
subtype innervates distinct target domains within different cortical neuronal subgroups [10,11,12,13,14,15,16]. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cerebral cortex, and most cortical inhibitory synapses originate from non-pyramidal cells [7,10,17,18,19,20]. This review summarizes the latest research findings concerning inhibitory GABAergic nonpyramidal cells, and explores their roles in the functional architecture of the cortical microcircuit.
Non-pyramidal cell subtypes Cortical microcircuitry is composed of pyramidal cells, non-pyramidal cells, and afferent neurons from the thalamus and other subcortical regions. These cell types are arranged in a well-ordered wiring pattern and establish the complex functional architecture of the microcircuit. A wide variety of neuronal subtypes are found in the neocortex. In particular, many different non-pyramidal cell subtypes exist, although they account for only 20% of all cortical neurons. Non-pyramidal cell subtypes are morphologically classified into basket cells, chandelier cells, Martinotti cells, double bouquet cells, neurogliaform cells, and others (Figure 1), according to their distinct axonal and dendritic arborization patterns [21,22,23]. Their morphological differences suggest that different non-pyramidal cell subtypes innervate different domains of target neurons, and this is indeed the case [10,14] (Figure 2). Distinct patterns of neurochemical marker expression such as parvalbumin (PV), calretinin (CR), somatostatin (SOM), vasoactive intestinal polypeptide (VIP) and different firing properties are also observed in cortical non-pyramidal cell subtypes (Figure 1) [7,9,24,25,26]. Morphologically distinct non-pyramidal cell subtypes possess certain combinations of markers and firing properties [7,24,26,27], and are active with specific timing during different states [28]. This suggests that each non-pyramidal cell subtype has a distinct role in the cortical microcircuit. The characteristics of the most prevalent GABAergic non-pyramidal subtypes are described below.
Target domains of non-pyramidal cells Non-pyramidal cells innervate three different target domains, soma, dendritic shaft, and dendrite spines, in different animal species including humans [12–15]. The functional significance of these three inhibition modalities is likely to be different. The somatic synapses may provide strong global control of pyramidal cell activity. IPSPs by dendritic shaft synapses are unlikely to conduct over long distances, effectively reducing only adjacent EPSPs [29]. They intercept local dendritic excitatory postsynaptic potentials and control integration of these Current Opinion in Neurobiology 2014, 26:7–14
8 Inhibition: Synapses, Neurons and Circuits
Figure 1 RS Martinotti SOM+
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Current Opinion in Neurobiology
Subtypes of cortical non-pyramidal cells. Upper panels show drawings of different subtypes of cortical non-pyramidal cells in different layers. Cell soma and dendrites are shown in black and axonal fibers are shown in red. Lower panels show examples of firing patterns after step-current injection into cortical non-pyramidal cell subtypes. FS, fast spiking; LS, late spiking; RS, regular spiking; SOM, somatostatin; AAc, alpha-actinin-2; CR, calretinin; CRF, corticotropin-releasing factor; VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin. Current Opinion in Neurobiology 2014, 26:7–14
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Untangling GABAergic wiring Kubota 9
Figure 2
elongated neurogliaform
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Summary diagram showing the cortical microcircuit. Inhibitory non-pyramidal cell subtypes innervate different domains of layer 5 pyramidal cells and other non-pyramidal cells. The thalamo-cortical fibers innervate spines contacted by inhibitory boutons. The other excitatory axon terminals are not shown. FS, fast spiking; RS/BS, regular/burst spiking; LS, late spiking; SOM, somatostatin; AAc, alpha-actinin-2; CR, calretinin; CRF, corticotropinreleasing factor; VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin; PV, parvalbumin; VVA, vicia villosa agglutinin; NPY, neuropeptide Y; NOS, nitric oxide synthase; SPR, substance P receptor.
potentials from more distal dendrites [30]. By contrast, synapses on spines have strictly local actions to veto excitatory inputs to that spine [31], and are known as thalamo-cortical excitatory efferents [14]. Thus, inhibitory synapses made at these three sites provide different forms of control over excitatory signals transmitted to pyramidal cells. Interestingly, among these three target domains, inhibitory dendritic spine synapses and their recipient spines are highly plastic, depending on the visual experience [32] and whisker stimulation [33].
layer 5 (L5) pyramidal neurons [10]. Basket cell axons primarily target the somata and proximal dendrites, while Martinotti cells target the apical tuft dendrites. Similarly, double-bouquet cells provide inhibition to the middle and distal basal dendrites, neurogliaform cells target secondary and tertiary tuft dendrites, and chandelier cells selectively inhibit axonal initial segments, and so on. However, these non-pyramidal cell subtypes may innervate other subdomains of other classes of target neuron [10,11].
Basket cells Many non-pyramidal cell subtypes selectively inhibit specific subcellular domains on target neurons. For instance, a variety of non-pyramidal neuron subtypes selectively inhibit nonoverlapping subcellular compartments of www.sciencedirect.com
Relative to other non-pyramidal neuron subtypes, basket cells preferentially innervate the somata of pyramidal neurons. In the rat cortex, >14% of basket neuron boutons arrive at somata [9,22]. On the other hand, Current Opinion in Neurobiology 2014, 26:7–14
10 Inhibition: Synapses, Neurons and Circuits
non-basket cells typically provide only few inputs onto somata (0–7%) [9,22]. PV-positive cells constitute one of the major non-pyramidal cell subtypes, and are mostly fast-spiking (FS) interneurons. PV-expressing cells mainly inhibit both pyramidal cells and PV-positive cells [19]. FS basket cells are the largest cell population among the PV-positive cells, and represent 40–50% of non-pyramidal cells [9,25,26,34,35]. Their axon fibers extend horizontally in a layer-specific manner from the soma, so called nest basket cell [36]. A few descending axon collaterals are extended, but these rarely innervate layer 1 (L1). Around 25% of the axon terminals of FS basket cells innervate cell soma [22]; other axon terminals innervate the dendrites and spine heads of target neurons [14]. The somatic inhibition effectively decreases the target cell activity. This pattern of innervation is similar to other cortical inhibitory interneurons, although not all subtypes innervate cell soma [14]. The FS basket cells of the rat cortex have 3000–5000 axonal boutons [22]. Each FS basket cell innervates target pyramidal cells with 5–15 terminal boutons, and is therefore estimated to innervate 200–1000 pyramidal cells. FS basket cells can fire repetitively at up to 400 Hz [37] because K+ channels containing Kv3.1 and Kv3.2 proteins allow sustained high-frequency firing [38–40]. However, functionally powerful autapses provide feedback inhibition that reduces excitability [41]. In in vivo conditions, FS basket cells fire repetitively at up to 30–50 Hz in the motor cortex during motor behavior [42], at up to 30 Hz in the prefrontal cortex during tail pinch [43], and at 20– 30 Hz in the hippocampus [44]. They also discharge rhythmically with spindle (7–14 Hz) and gamma (30– 80 Hz) oscillations [45], so firing frequency is well controlled in vivo. About 80% of PV-positive cells, mostly FS basket cells, express connexin 36 [46], which forms an electrical synapse using gap junctions to connect with other FS basket cells, with a coupling coefficient of around 0.02 [47–49]. Each PV-positive cell has around 60 gap junctions [50]. Synchronization of FS basket cell activity through the electrical coupling via gap junctions will reinforce the population inhibition in the cortical microcircuit. Non-FS basket cell subtype population expresses CR, cholecystokinin (CCK), VIP, and/or corticotropin-releasing factor (CRF) and show regular or burst spiking (RS/ BS) patterns [11]. They are subdivided into three groups, large basket cells, which express CCK only, small basket or descending basket cells [22,36]. Thirty-seven percent of CR/VIP/CCK-positive basket cells also express connexin 36 [46], and therefore may connect with each other through electrical synapses. Large basket cells have 2000–4000 axonal boutons, while small basket cells have 1000–2500 boutons [22]; therefore, they may innervate 100–500 neurons. RS/BS CCK-positive cells may also express the cannabinoid receptor (CB1R) [51,52], resulting in a difference in activity compared with FS basket Current Opinion in Neurobiology 2014, 26:7–14
cells. On subtle and repetitive excitation, CB1R-positive basket cells respond late and do not show repetitive response, while FS basket cells respond immediately and repetitively [53,54]. CCK-expressing basket cells also release GABA more asynchronously than FS basket cells [55]. Two different basket cell subtypes respond complimentary to the repetitive signals. It suggests that they have different functional roles in cortical microcircuit architecture [56]. Basket cells with late spiking (LS) properties are also found in the cortex [22]. Their axons and dendrites branch less frequently than those of the other basket cells, and are sparsely distributed in their dendritic and axonal fields (Figure 1).
Martinotti and related cells The second largest non-pyramidal cell subtype is SOMpositive cells, which comprise 20–30% of the non-pyramidal cell population [9,25,26,34,35]. They show low threshold spike or RS/BS firing patterns, and express neuropeptide Y (NPY), nitric oxide synthase (NOS), substance P receptor (SPR), and/or calbindin D28k [9,25,26,34,35], in addition to SOM. Most are Martinotti cells, which display ascending axonal arborization to L1, with SOM/NPY/calbindin D28k expression. They mainly innervate the apical and tuft dendrites of pyramidal cells [10,57,58]. Martinotti cells inhibit calcium spikes in L5 tuft dendrites [59] and also inhibit all other interneurons [19]. Approximately 10–25% of SOM-positive cells and 15–45% of NPY-positive cells also express both NOS and SPR [25,26,60]. This subtype showing SOM/NPY/ NOS/SPR expression loses spines during development [26] and known to extend long projecting axons to other cortical areas [18,61], those characteristics differs from the Martinotti cells, which have many spines on their dendrites and ascending axons to L1. Around half of all SOMpositive cells express connexin 36 [46] and are electrically coupled to cells of a similar subtype to enhance synchronized activity [48].
Double bouquet and related cells The third major non-pyramidal cell subtype are double bouquet cells and related cells, which have descending axonal fibers. They constitute 15–35% of the non-pyramidal cell population of the cortical microcircuit [9,25,26,34,35]. They show RS/BS properties and express VIP, CRF, CR, serotonin 5-hydroxytryptamine 3A receptor (5-HT3A), or CCK [25,26,62]. Co-express patterns of those neurochemical markers depend on the layers. For instance, about 60% of this subtype cells express both CRF and VIP, 40% cells express only CR, and all express 5-HT3A in L2/3. CR-positive interneurons in the rat hippocampus innervate other interneurons [63]. In the primary somatosensory cortex (S1), VIP/5-HT3Apositive double bouquet cells receive excitatory signals from the primary motor cortex (M1) and in turn innervate www.sciencedirect.com
Untangling GABAergic wiring Kubota 11
mainly SOM-positive Martinotti cells and L5 pyramidal cells. The SOM-positive inhibitory cells then innervate the L5 pyramidal cells. VIP/5-HT3A-positive cells and SOM-positive cells also innervate PV-positive FS basket cells, which are driven by excitatory signals from M1 and innervate the pyramidal cells with feedforward inhibition (personal communication from Dr. SooHyun Lee) [19,62,64]. This subtype is primarily responsible for the control of other non-pyramidal cells.
Neurogliaform and related cells Neurogliaform cells express alpha-actinin-2 (AAc) and NPY, weakly express NOS, and exhibit LS membrane properties [9,26,60,65]. NPY-expressing neurons in layers 2/3–6 co-express either AAc or SOM but not both [9]. Therefore, NPY-positive cells are classified into neurogliaform (i.e., AAc-containing), Martinotti (i.e., SOM-containing) or NOS cell (i.e., NOS-containing and SOM-containing). They have more primary dendrites and more frequent branching points, and consequently a smaller dendritic field, than other non-pyramidal cell subtypes [23]. This subtype has the longest axon length (about 30 mm) of the non-pyramidal cells, and short interbouton intervals. This results in high bouton density in the axonal field. Neurogliaform cells are a possible source of slow inhibition due to their action on metabotropic GABAB receptors [66]. Two related cell subgroups are found in L1. AAc-only cells resemble neurogliaform cells, with extensive local axon ramification and a large number of primary dendrites with frequent branching, but axons are extended horizontally among L1. They are therefore known as elongated neurogliaform cells, and most show LS nonadapting firing properties [10,26]. The other L1 subgroups are AAc/CR-positive cells resembling LS basket cells, with sparsely distributed axons, descending axonal arbors, and horizontally extended dendrites. These are called single-bouquet cells, and they mostly show adapting non-LS firing properties [10,26]. In rats, these L1 interneurons are excited by callosal excitatory axonal fibers after ipsilateral hindlimb stimulation, and inhibit spiking activity of L5 pyramidal cell with GABABmediated inhibition in vivo [67]. They exert functionally different properties to inhibit L5 pyramidal cells [56]. The single-bouquet cells disinhibit L5 pyramidal cells via L2/3 interneurons, and the elongated neurogliaform cells inhibit both L5 pyramidal cell and L2/3 interneuron and functionally this inhibitory connections reduce the dendritic complex spike generation in L5 pyramidal cells (Figure 2) [10].
Chandelier cells FS chandelier cells, a minor FS cell population that express PV, almost exclusively innervate the initial segments of pyramidal cell axons, with vertically oriented axon-terminal bouton alignment [11,68]. Chandelier cells www.sciencedirect.com
fire at the troughs of pyramidal cell discharges, slightly faster than basket cell discharges, during theta rhythm generation in the hippocampus [28]. FS chandelier cells are believed to inhibit pyramidal cell activity by releasing the inhibitory neurotransmitter GABA; this should have a hyperpolarizing or shunting postsynaptic effect on the target pyramidal cell and efficiently suppress the target cell activity [69]. However, chandelier cells may excite postsynaptic pyramidal cells under certain conditions due to the nature of the membrane of the axon initial segment of the target pyramidal cell, which has a low potassium chloride co-transporter 2 (KCC2) distribution [70]. This may induce an influx of chloride ions ([Cl ]in) into the cytosol of the axon initial segment, which leads to the depolarizing effects of GABA [71,72]. However, this result is inconsistent with the population activity timing of pyramidal and chandelier cells during theta rhythm oscillation, in which chandelier cells discharge during the trough of pyramidal cell discharges [28], and with a local unitary field analysis of spike discharge of axo-axonic cells in the hippocampus [73]. Target pyramidal cell inhibition or excitation appears to depend on the postsynaptic membrane potential, which may vary under different conditions [74]. Chandelier cells are electrically coupled with each other, with a coupling coefficient of about 0.05 [74,75]. This suggests chandelier cells discharge synchronously to reduce the target pyramidal cell population activity effectively. Chandelier cells without FS firing properties/PV expression are also found, and these cells express CRF [65,75,76].
Connection selectivity PV-positive FS basket cells and SOM-positive Martinotti cells non-selectively innervate surrounding pyramidal cells [77,78] and are not involved in the fine-scale network of the cortical microcircuit [79]. In primary visual cortex, unlike excitatory pyramidal cells, non-pyramidal cells do not show orientation tuning [80,81]. However their dendrites show pronounced orientation tuned domains, individual dendritic branches often have multiple domains with distinct preferred orientations [82], which receive convergent input from nearby pyramidal cells with a broad range of preferred orientations [83]. These results indicate that, unlike excitatory pyramidal cells, non-pyramidal cells are not involved in connection selectivity of functional cortical microcircuitry [84,85].
Concluding remarks Cortical GABAergic non-pyramidal cells are heterogeneous in terms of dendritic and axonal morphology, synaptic connections, physiological properties, and neurochemical expression. Each subtype is likely to have a different functional role in regulating cortical microcircuit activity. Most non-pyramidal cell subtypes have been identified based on morphological, neurochemical, and physiological differences. It will be of great interest to Current Opinion in Neurobiology 2014, 26:7–14
12 Inhibition: Synapses, Neurons and Circuits
further investigate their functional as well as anatomical synaptic wiring in the cortical microcircuit.
Acknowledgements We thank Drs. Yasuo Kawaguchi and Fuyuki Karube for Neurolucida neuron drawings and Dr. Allan T Gulledge for comments. This work was supported by JSPS KAKENHI (Grant numbers 24120718 and 25290012) from the MEXT of Japan.
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14 Inhibition: Synapses, Neurons and Circuits
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