Abstract
Synaptic inhibition can be viewed as a counterbalance of synaptic excitation. However, mul-tiple recent studies at the cellular and network level show that inhibition serves a variety of additional, highly specific functions in the mammalian nervous system. At the molecular and cellular level, inhibitory synapses express diverse postsynaptic reversal potentials, kinetics, plasticity, and pharmacological modulation. This heterogeneity corresponds to the complexity of inhibition at the network level, where interneurons are now perceived as diverse and highly specific organizers of coherent activity patterns. We review some important new developments in the molecular, cellular and network physiology of inhibition. It turns out that understanding inhibition is a key to understanding neuronal network behaviour and, ultimately, may provide important clues for the development of novel therapeutic strategies in neuro-psychiatric diseases.
References
-
1
Alle H, Geiger JR.
GABAergic spill-over transmission onto hippocampal mossy fiber boutons.
J Neurosci.
2007;
27
(4)
942-950
-
2
Ascoli GA, onso-Nanclares L, Anderson SA. et al .
Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex.
Nat Rev Neurosci.
2008;
9
(7)
557-568
-
3
Axmacher N, Stemmler M, Engel D. et al .
Transmitter metabolism as a mechanism of synaptic plasticity: a modeling study.
J Neurophysiol.
2004;
91
(1)
25-39
-
4
Bak LK, Schousboe A, Waagepetersen HS.
The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.
J Neurochem.
2006;
98
(3)
641-653
-
5
Banks MI, Pearce RA.
Kinetic differences between synaptic and extrasynaptic GABAA receptors in CA1 pyramidal cells.
J Neurosci.
2000;
20
(3)
937-948
-
6
Bartos M, Vida I, Frotscher M. et al .
Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network.
J Neurosci.
2001;
21
(8)
2687-2698
-
7
Bartos M, Vida I, Frotscher M. et al .
Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks.
Proc Natl Acad Sci USA.
2002;
99
(20)
13222-13227
-
8
Beau FEN, Alger BE.
Transient suppression of GABAA-receptor-mediated IPSPs after epileptiform burst discharges in CA1 pyramidal cells.
J Neurophysiol.
1998;
79
(2)
659-669
-
9
Ben-Ari Y.
Excitatory actions of GABA during development: the nature of the nurture.
Nat Rev Neurosci.
2002;
3
(9)
728-739
-
10
Ben-Ari Y, Cherubini E, Corradetti R. et al .
Giant synaptic potentials in immature rat CA3 hippocampal neurones.
J Physiol.
1989;
416
303-325
-
11
Ben-Ari Y, Tseeb V, Raggozzino D. et al .
Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life.
Prog Brain Res.
1994;
102
261-273
-
12
Blaesse P, Airaksinen MS, Rivera C. et al .
Cation-chloride cotransporters and neuronal function.
Neuron.
2009;
61
(6)
820-838
-
13
Bormann J, Feigenspan A.
GABAC receptors.
Trends Neurosci.
1995;
18
(12)
515-519
-
14
Bormann J, Hamill OP, Sakmann B.
Mechanism of anion permeation through channels gated by glycine and γ-aminobutyric acid in mouse cultured spinal neurones.
J Physiol.
1987;
385
243-286
-
15
Bouilleret V, Loup F, Kiener T. et al .
Early loss of interneurons and delayed subunit-specific changes in GABAA-receptor expression in a mouse model of mesial temporal lobe epilepsy.
Hippocampus.
2000;
10
(3)
305-324
-
16
Brickley SG, Revilla V, Cull-Candy SG. et al .
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
Nature.
2001;
409
(6816)
88-92
-
17
Buhl EH, Otis TS, Mody I.
Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model.
Science.
1996;
271
(5247)
369-373
-
18
Buzsaki G, Csicsvari J, Dragoi G. et al .
Homeostatic maintenance of neuronal excitability by burst discharges in vivo.
Cereb Cortex.
2002;
12
(9)
893-899
-
19
Buzsáki G, Draguhn A.
Neuronal oscillations in cortical networks.
Science.
2004;
304
(5679)
1926-1929
-
20
Caraiscos VB, Elliott EM, You-Ten KE. et al .
Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors.
Proc Natl Acad Sci USA.
2004;
101
(10)
3662-3667
-
21
Cavelier P, Hamann M, Rossi D. et al .
Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences.
Prog Biophys Mol Biol.
2005;
87
(1)
3-16
-
22
Cohen I, Navarro V, Clemenceau S. et al .
On the origin of interictal activity in human temporal lobe epilepsy in vitro.
Science.
2002;
298
(5597)
1418-1421
-
23
Conti F, DeBiasi S, Minelli A. et al .
EAAC1, a high-affinity glutamate tranporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex.
Cereb Cortex.
1998;
8
(2)
108-116
-
24
Cossart R, Dinocourt C, Hirsch JC. et al .
Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy.
Nat Neurosci.
2001;
4
(1)
52-62
-
25
Coulter DA.
Epilepsy-associated plasticity in γ-aminobutyric acid receptor expression, function, and inhibitory synaptic properties.
Int Rev Neurobiol.
2001;
45
237-252
-
26
De Gois S, Schäfer MKH, Defamie N. et al .
Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits.
J Neurosci.
2005;
25
(31)
7121-7133
-
27
Draguhn A, Axmacher N, Kolbaev S.
Presynaptic ionotropic GABA receptors.
Results Probl Cell Differ.
2008;
44
69-85
-
28
Durstewitz D, Deco G.
Computational significance of transient dynamics in cortical networks.
Eur J Neurosci.
2008;
27
(1)
217-227
-
29
Durstewitz D, Seamans JK.
The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia.
Biol Psychiatry.
2008;
64
(9)
739-749
-
30
Eccles JC, Schmidt RF, Willis WD.
Presynaptic inhibition of the spinal monosynaptic reflex pathway.
J Physiol.
1962;
161
282-297
-
31
Engel D, Pahner I, Schulze K. et al .
Plasticity of rat central inhibitory synapses through GABA metabolism.
J Physiol.
2001;
535
(2)
473-482
-
32
Erickson JD, De Gois S, Varoqui H. et al .
Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size.
Neurochem Int.
2006;
48
(6–7)
643-649
-
33
Esclapez M, Houser CR.
Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy.
J Comp Neurol.
1999;
412
(3)
488-505
-
34
Farrant M, Nusser Z.
Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors.
Nat Rev Neurosci.
2005;
6
(3)
215-229
-
35
Feldblum S, Ackermann RF, Tobin AJ.
Long-term increase of glutamate decarboxylase mRNA in a rat model of temporal lobe epilepsy.
Neuron.
1990;
5
(3)
361-371
-
36
Freund TF, Buzsaki G.
Interneurons of the hippocampus.
Hippocampus.
1996;
6
(4)
347-470
-
37
Fricke MN, Jones-Davis DM, Mathews GC.
Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission.
J Neurochem.
2007;
102
(6)
1895-1904
-
38
Fritschy J-M.
Epilepsy, E/I balance and GABAA receptor plasticity.
Front Mol Neurosci.
2008;
1 (article 5)
-
39
Gabriel S, Njunting M, Pomper JK. et al .
Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis.
J Neurosci.
2004;
24
(46)
10416-10430
-
40
Garraghty PE, Lachica EA, Kaas JH.
Injury-induced reorganization of somatosensory cortex is accompanied by reductions in GABA staining.
Somatosens Mot Res.
1991;
8
(4)
347-354
-
41
Glickfeld LL, Roberts JD, Somogyi P. et al .
Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis.
Nat Neurosci.
2009;
12
(1)
21-23
-
42
Glykys J, Mann EO, Mody I.
Which GABAA receptor subunits are necessary for tonic inhibition in the hippocampus?.
J Neurosci.
2008;
28
(6)
1421-1426
-
43
Glykys J, Mody I.
The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus.
J Physiol.
2007;
582
(3)
1163-1178
-
44
Grewe BF, Helmchen F.
Optical probing of neuronal ensemble activity.
Curr Opin Neurobiol.
2009;
19
(5)
520-529
-
45
Gulledge AT, Stuart GJ.
Excitatory actions of GABA in the cortex.
Neuron.
2003;
37
(2)
299-309
-
46
Hartmann K, Bruehl C, Golovko T. et al .
Fast homeostatic plasticity of inhibition via activity-dependent vesicular filling.
PLoS One.
2008;
3
(8)
e2979
-
47
Hevers W, Lüddens H.
The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes.
Mol Neurobiol.
1998;
18
(1)
35-86
-
48
Holmgren CD, Mukhtarov M, Malkov AE. et al .
Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro.
J Neurochem.
2009;
-
49
Jin H, Wu H, Osterhaus G. et al .
Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles.
Proc Natl Acad Sci USA.
2003;
100
(7)
4293-4298
-
50
Jinno S, Klausberger T, Marton LF. et al .
Neuronal diversity in GABAergic long-range projections from the hippocampus.
J Neurosci.
2007;
27
(33)
8790-8804
-
51
Kaila K, Voipio J.
Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance.
Nature.
1987;
330
(6144)
163-165
-
52
Katz LC, Shatz CJ.
Synaptic activity and the construction of cortical circuits.
Science.
1996;
274
(5290)
1133-1138
-
53
Klausberger T, Magill PJ, Márton LF. et al .
Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo.
Nature.
2003;
421
(6925)
844-848
-
54
Klausberger T, Somogyi P.
Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.
Science.
2008;
321
(5885)
53-57
-
55
Kullmann DM, Ruiz A, Rusakov DM. et al .
Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why?.
Prog Biophys Mol Biol.
2005;
87
(1)
33-46
-
56
Lamsa K, Heeroma JH, Kullmann DM.
Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination.
Nat Neurosci.
2005;
8
(7)
916-924
-
57
Leschinger A, Stabel J, Igelmund P. et al .
Pharmacological and electrographic properties of epileptiform activity induced by elevated K+ and lowered Ca2+ and Mg2+ concentration in rat hippocampal slices.
Exp Brain Res.
1993;
96
(2)
230-240
-
58
Leutgeb JK, Leutgeb S, Moser M-B. et al .
Pattern separation in the dentate gyrus and CA3 of the hippocampus.
Science.
2007;
315
(5814)
961-966
-
59
Lewis DA, Sweet RA.
Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies.
J Clin Invest.
2009;
119
(4)
706-716
-
60
Liang S-L, Carlson GC, Coulter DA.
Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1.
J Neurosci.
2006;
26
(33)
8537-8548
-
61
Lin L, Osan R, Shoham S. et al .
Identification of network-level coding units for real-time representation of episodic experiences in the hippocampus.
Proc Natl Acad Sci USA.
2005;
102
(17)
6125-6130
-
62
Lisman JE, Coyle JT, Green RW. et al .
Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
Trends Neurosci.
2008;
31
(5)
234-242
-
63
Logothetis NK, Pauls J, Augath M. et al .
Neurophysiological investigation of the basis of the fMRI signal.
Nature.
2001;
412
(6843)
150-157
-
64
Mann EO, Paulsen O.
Role of GABAergic inhibition in hippocampal network oscillations.
Trends Neurosci.
2007;
30
(7)
343-349
-
65
Mathews GC, Diamond JS.
Neuronal glutamate uptake contributes to GABA synthesis and inhibitory synaptic strength.
J Neurosci.
2003;
23
(6)
2040-2048
-
66
Melone M, Quagliano F, Barbaresi P. et al .
Localization of the glutamine transporter SNAT1 in rat cerebral cortex and neighboring structures, with a note on its localization in human cortex.
Cereb Cortex.
2004;
14
(5)
562-574
-
67
Misgeld U, Bijak M, Jarolimek W.
A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system.
Prog Neurobiol.
1995;
46
(4)
423-462
-
68
Mody I.
Distinguishing between GABAA receptors responsible for tonic and phasic conductances.
Neurochem Res.
2001;
26
(8–9)
907-913
-
69
Mody I, Pearce RA.
Diversity of inhibitory neurotransmission through GABAA receptors.
Trends Neurosci.
2004;
27
(9)
569-575
-
70
Morales-Aza BM, Chillingworth NL, Payne JA. et al .
Inflammation alters cation chloride cotransporter expression in sensory neurons.
Neurobiol Dis.
2004;
17
(1)
62-69
-
71
Niessing J, Ebisch B, Schmidt KE. et al .
Hemodynamic signals correlate tightly with synchronized gamma oscillations.
Science.
2005;
309
(5736)
948-951
-
72
Olah S, Fule M, Komlosi G. et al .
Regulation of cortical microcircuits by unitary GABA-mediated volume transmission.
Nature.
2009;
461
(7268)
1278-1281
-
73
Pearce RA.
Physiological evidence for two distinct GABAA responses in rat hippocampus.
Neuron.
1993;
10
(2)
189-200
-
74
Pinault D.
A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or Neurobiotin.
J Neurosci Meth.
1996;
65
(2)
113-136
-
75
Qi Z, Miller GW, Voit EO.
A mathematical model of presynaptic dopamine homeostasis: implications for schizophrenia.
Pharmacopsychiatry.
2008;
41
(S 01)
S89-S98
-
76
Qi Z, Miller GW, Voit EO.
Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals.
Synapse.
2009;
63
(12)
1133-1142
-
77
Rheims S, Holmgren CD, Chazal G. et al .
GABA action in immature neocortical neurons directly depends on the availability of ketone bodies.
J Neurochem.
2009;
110
(4)
1330-1338
-
78
Rivera C, Voipio J, Payne JA. et al .
The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation.
Nature.
1999;
397
(6716)
251-255
-
79
Rivera C, Voipio J, Thomas-Crusells J. et al .
Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2.
J Neurosci.
2004;
24
(19)
4683-4691
-
80
Rudolph U, Möhler H.
Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
Annu Rev Pharmacol Toxicol.
2004;
44
475-498
-
81
Rudolph U, Möhler H.
GABA-based therapeutic approaches: GABAA receptor subtype functions.
Curr Opin Pharmacol.
2006;
6
(1)
18-23
-
82
Rudomin P, Schmidt RF.
Presynaptic inhibition in the vertebrate spinal cord revisited.
Exp Brain Res.
1999;
129
(1)
1-37
-
83
Ruiz A, Fabian-Fine R, Scott R. et al .
GABAA receptors at hippocampal mossy fibers.
Neuron.
2003;
39
(6)
961-973
-
84
Rupprecht R, Rammes G, Eser D. et al .
Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects.
Science.
2009;
325
(5939)
490-493
-
85
Schuchmann S, Schmitz D, Rivera C. et al .
Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis.
Nat Med.
2006;
12
(7)
817-823
-
86
Scimemi A, Andersson A, Heeroma JH. et al .
Tonic GABAA receptor-mediated currents in human brain.
Eur J Neurosci.
2006;
24
(4)
1157-1160
-
87
Seamans JK, Gorelova N, Durstewitz D. et al .
Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons.
J Neurosci.
2001;
21
(10)
3628-3638
-
88
Semyanov A, Walker MC, Kullmann DM. et al .
Tonically active GABAA receptors: modulating gain and maintaining the tone.
Trends Neurosci.
2004;
27
(5)
262-269
-
89
Shu Y, Hasenstaub A, McCormick DA.
Turning on and off recurrent balanced cortical activity.
Nature.
2003;
423
(6937)
288-293
-
90
Somogyi P, Klausberger T.
Defined types of cortical interneurone structure space and spike timing in the hippocampus.
J Physiol.
2005;
562
(1)
9-26
-
91
Staley KJ, Proctor WR.
Modulation of mammalian dendritic GABAA receptor function by the kinetics of Cl− and HCO3
− transport.
J Physiol.
1999;
519
(3)
693-712
-
92
Staley KJ, Soldo BL, Proctor WR.
Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors.
Science.
1995;
269
(5226)
977-981
-
93
Stein V, Hermans-Borgmeyer I, Jentsch TJ. et al .
Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride.
J Comp Neurol.
2004;
468
(1)
57-64
-
94
Sung K-W, Kirby M, McDonald MP. et al .
Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice.
J Neurosci.
2000;
20
(20)
7531-7538
-
95
Szabadics J, Varga C, Molnar G. et al .
Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits.
Science.
2006;
311
(5758)
233-235
-
96
Traub RD, Bibbig A, LeBeau FEN. et al .
Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro.
Annu Rev Neurosci.
2004;
27
247-278
-
97
Traub RD, Wong RKS.
Cellular mechanism of neuronal synchronization in epilepsy.
Science.
1982;
216
(4547)
745-747
-
98
Tretter F, Albus M.
Systems biology and psychiatry – modeling molecular and cellular networks of mental disorders.
Pharmacopsychiatry.
2008;
41
(S 01)
S2-S18
-
99
Turrigiano GG.
Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same.
Trends Neurosci.
1999;
22
(5)
221-227
-
100
Turrigiano GG, Nelson SB.
Hebb and homeostasis in neuronal plasticity.
Curr Opin Neurobiol.
2000;
10
(3)
358-364
-
101
Whittington MA, Traub RD.
Interneuron Diversity series: inhibitory interneurons and network oscillations in vitro.
Trends Neurosci.
2003;
26
(12)
676-682
-
102
Whittington MA, Traub RD, Kopell N. et al .
Inhibition-based rhythms: experimental and mathematical observations on network dynamics.
Int J Psychophysiol.
2000;
38
(3)
315-336
-
103
Wilson RI, Kunos G, Nicoll RA.
Presynaptic specificity of endocannabinoid signaling in the hippocampus.
Neuron.
2001;
31
(3)
453-462
-
104
Wilson RI, Nicoll RA.
Endocannabinoid signaling in the brain.
Science.
2002;
296
(5568)
678-682
-
105
Wilson RI, Nicoll RA.
Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.
Nature.
2001;
410
(6828)
588-592
-
106
Woo TU, Whitehead RE, Melchitzky DS. et al .
A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia.
Proc Natl Acad Sci USA.
1998;
95
(9)
5341-5346
-
107
Woo TU, Whitehead RE, Melchitzky DS. et al .
A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia.
Proc Natl Acad Sci USA.
1998;
95
(9)
5341-5346
-
108
Woodruff A, Xu Q, Anderson SA. et al .
Depolarizing effect of neocortical chandelier neurons.
Front Neural Circuits.
2009;
3
15
-
109
Yamada J, Khirug S, Voipio L. et al .
The GABAergic depolarization of the axon initial segment in cortical principal neurons is mediated by the Na-K-2Cl cotransporter NKCC1.
The Society for Neuroscience Abstracts.
2007;
683.6/G48
-
110
Zhang Z, Sun J, Reynolds GP.
A selective reduction in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia patients.
Chin Med J (Engl).
2002;
115
(6)
819-823
Correspondence
Prof. Dr. A. Draguhn
Institute of Physiology and Pathophysiology
University of Heidelberg
Im Neuenheimer Feld 326
69120 Heidelberg
Germany
Phone: +49-6221-544056
Fax: +49-6221-546364
Email: andreas.draguhn@physiologie.uni-heidelberg.de
