Plasticity of Inhibition Dimitri M. Kullmann, Alexandre W. Moreau, Yamina Bakiri, Elizabeth Nicholson  Neuron  Volume 75, Issue 6, Pages 951-962 (September 2012) DOI: 10.1016/j.neuron.2012.07.030 Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 1 Endocannabinoid-Mediated Retrograde Signaling at GABAergic Synapses Synthesis of the endocannabinoid 2-AG by the phospholipase Cβ (PLC)-diacylglycerol lipase (DGL) pathway can be triggered by Ca2+ influx via voltage-gated Ca2+ channels (VGCCs) but also by activation of Gq/11-coupled muscarinic M1/M3 or group I mGluRs via a cascade involving inositol trisphosphate receptors. 2-AG is thought to depress GABA release by inhibiting presynaptic VGCCs and is degraded by monoacylglycerol lipase. The alternative endocannabinoid anandamide has been implicated in retrograde signaling at some synapses and is mainly broken down by fatty acid amyl hydrolase. iLTD can be triggered by activity at nearby excitatory synapses together with firing of GABAergic terminals. Its effector mechanisms involve presynaptic RIM1α and calcineurin at GABAergic terminals. Other retrograde messengers reported at inhibitory synapses include BDNF, nitric oxide, and glutamate, although most of these trigger an increase in GABA release. Neuron 2012 75, 951-962DOI: (10.1016/j.neuron.2012.07.030) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 2 Mechanisms Underlying Changes in GABAA Receptor Function The trafficking, lateral mobility, and phosphorylation of GABAA receptors all vary with neuronal activity, with multiple kinases implicated, resulting in either increases or decreases in GABAergic currents. Epilepsy is also associated with changes in the subunit composition of GABA receptors. The Cl− equilibrium potential can also be altered in an activity-dependent manner, principally by changes in function or trafficking of the transporter KCC2. Neuron 2012 75, 951-962DOI: (10.1016/j.neuron.2012.07.030) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 3 LTP and LTD at Glutamatergic Synapses on Interneurons Both NMDAR-independent (A) and NMDAR-dependent (B) forms of plasticity occur at many glutamatergic synapses on interneurons. (A) NMDAR-independent plasticity requires postsynaptic group I mGluRs and Ca2+-permeable rectifying AMPARs and, at some synapses, is preferentially induced when the postsynaptic neuron is at a relatively negative potential (anti-Hebbian LTP). Other ion channels (L-type VGCCs, nicotinic receptors) can influence the balance of LTP and LTD. Although most studies have reported that expression is presynaptic, the retrograde messengers have not been conclusively identified. (B) The conjunction of pre- and postsynaptic depolarization or activity leads to NMDAR-dependent “Hebbian” LTP at some synapses, the expression of which is likely to be postsynaptic. The relative roles of AMPAR trafficking and phosphorylation are not known. Although CaMKIIα is absent, a related kinase is likely to play a role in NMDAR-dependent LTP. Neuron 2012 75, 951-962DOI: (10.1016/j.neuron.2012.07.030) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 4 A Possible Developmental Role of Plasticity of Inhibition Plasticity of inhibition is likely to contribute to the emergence of balanced excitation (blue) and inhibition (red) observed in many feedforward projections in the CNS. Maturation of such circuits is associated with a gradual shift away from burst firing of principal cells toward a sparse-firing regime in which excitatory and inhibitory currents are temporally correlated (indicated schematically as inward and outward currents, IExc and IInh). Such a redistribution of inhibition of principal cells may be achieved by changes in both glutamatergic synapses on interneurons and GABAergic synapses on pyramidal neurons (indicated schematically as changes in bouton size). Several other computational roles have been proposed for plasticity of inhibition, including refinement of lateral inhibition or temporal discrimination, release from inhibition mediated by CCK-positive interneurons, and habituation to sensory inputs. Neuron 2012 75, 951-962DOI: (10.1016/j.neuron.2012.07.030) Copyright © 2012 Elsevier Inc. Terms and Conditions