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# Editorial: Plasticity of GABAergic synapses

Andrea Barberis, Alberto Bacci

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Andrea Barberis, Alberto Bacci. Editorial: Plasticity of GABAergic synapses. Frontiers in Cellular Neuroscience, 2015, 9, pp.262. 10.3389/fncel.2015.00262. hal-01215424

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# Editorial: Plasticity of GABAergic synapses

Andrea Barberis¹* and Alberto Bacci²,³*

¹Neuroscience and Brain Technologies, Post-synaptic Mechanisms of GABAergic Transmission, Fondazione Istituto Italiano di Tecnologia, Genova, Italy, ²Inserm U 1127, Centre National de la Recherche Scientifique UMR 7225, Sorbonne Universités UPMC Paris 06, UMR S 11, Paris, France, ³Institut du Cerveau et de la Moelle Épinière, Paris, France

**Keywords:** inhibitory plasticity, ILTP, inhibitory synapse, GABAA receptors, inhibitory microcircuits

For long time, plasticity of brain circuits has been hypothesized to mainly rely on the flexibility of glutamatergic excitatory synapses, whereas inhibitory synapses have been assumed to be relatively invariant. Based on this view, inhibition should be exclusively modulated by the differential glutamatergic-driven activation of a highly diverse population of inhibitory interneurons displaying specific temporal dynamics and selective innervation patterns. However, it has been demonstrated that inhibitory synapses undergo several forms of plasticity, thus providing an additional source of versatility to the regulation of the neuronal network and the emergence of complex brain states.

The cellular and molecular mechanisms occurring at inhibitory synapses during the induction/expression of inhibitory short- and long-term synaptic plasticity are now beginning to be unraveled. At the presynaptic side, retrograde synaptic messengers modulate GABA release (Mendez and Bacci, 2011; Iremonger et al., 2013; Lourenco et al., 2014; Younts and Castillo, 2014), whereas postsynaptic plasticity typically involves changes in the number/gating properties of post-synaptic GABAA receptors (Kurotani et al., 2008; Houston et al., 2009; Luscher et al., 2011; Petrini et al., 2014; Flores et al., 2015). In addition, acute or chronic alterations of intracellular chloride concentration modulate the driving force of GABAergic currents and the subunit composition of GABAA receptors (Woodin et al., 2003; Raimondo et al., 2012; Succol et al., 2012).

The 14 articles presented in this ebook (including hypothesis and theory, minireviews, reviews, and original research articles) cover the mechanisms of inhibitory synaptic plasticity, at the molecular and microcircuit levels. Zacchi et al. (2014) focus on the signaling pathways controlling the phosphorylation state of gephyrin, a key scaffold protein at inhibitory synapses responsible for the synaptic clustering of both glycine and GABAA receptors. By considering the synapse as a highly dynamic element, Petrini and Barberis (2014), review the recent literature addressing the role of protein diffusion in the reorganization of the inhibitory postsynaptic density during inhibitory synaptic plasticity. A similar conceptual approach, based on the analysis of receptor dynamics, has been adopted by Muir and Kittler (2014) to investigate inhibitory plasticity in relation to GABAA receptor diffusion at inhibitory synapses located in the axon initial segment. This original research article reports that chronic depolarization increases the lateral mobility of GABAA receptors and reduces the size of post-synaptic GABAA receptor clusters, thus critically interfering with neuronal excitability. Hirano and Kawaguchi (2014) review another form of postsynaptic inhibitory plasticity observed at cerebellar synapses formed by stellate cells onto Purkinje cells. This inhibitory long-term potentiation involves the CaMKII-dependent increase of GABAA receptor signaling through direct GABAA receptor phosphorylation and/or promoted surface delivery via a GABARAP-dependent mechanism. In their original article, Gao et al. (2014) further address the molecular mechanisms of the aforementioned long-term inhibitory plasticity at cerebellar Purkinje cells. They report that the pathway of iLTP induction critically depends on the coordinated action of both αCaMKII and βCaMKII isoforms, and is modulated by the activation of GABAB receptors.

**OPEN ACCESS**

Edited and reviewed by:

Egidio D'Angelo,
University of Pavia, Italy

*Correspondence:

Andrea Barberis and Alberto Bacci,
andrea.barberis@iit.it;
alberto.bacci@icm-institute.org

Received: 03 June 2015

Accepted: 23 June 2015

Published: 07 July 2015

Citation:

Barberis A and Bacci A (2015)

Editorial: Plasticity of GABAergic synapses.
Front. Cell. Neurosci. 9:262.
doi: 10.3389/fncel.2015.00262
Flores et al. (2015) provide a broad yet detailed analysis of the molecular organization of inhibitory post-synaptic density. In addition, they highlight the formation and elimination of GABAergic synapses as an important source of inhibitory synaptic plasticity. The mini review by Maguire (2014) examines the plasticity of inhibition in response to acute and chronic stress involving region-specific changes of GABAA receptor subunit expression and alterations of the chloride gradient. Moreover, Dr. Maguire reports that stress acts as a metaplastic switch by enabling iLTP at parvocellular neuroendocrine cells (PNCs). Mapelli et al. (2015) provide a comprehensive overview of diverse forms of plasticity at specific cerebellar sub-circuits, introducing the concept of the coordination between excitatory and inhibitory plasticity for correct circuit functioning. In their minireview, Chevaleyre and Piskorowski (2014) highlight the importance of short- and long-term changes of inhibitory synaptic strength in tuning the threshold for the induction of excitatory plasticity. In addition, they discuss how plasticity of glutamatergic synapses onto PV+ interneurons shapes inhibition at hippocampal microcircuits. Pallotto and Deprez (2014) analyze the influence of inhibition in adult neurogenesis in the olfactory bulb and dentate gyrus, by discussing the role of GABAergic signaling in the development and plasticity of adult-born neurons. In their comprehensive review Griffen and Maffei (2014) examine different forms of pre- and post-synaptic inhibitory plasticity occurring at diverse somatosensory cortex interneuron subtypes and discuss the role of such plasticity in sensory cortical activity.

Synaptic signaling does not only depend on pre- or post-synaptic determinants but is also shaped by the dynamics of neurotransmitter in the synaptic cleft. The minireview and the hypothesis and theory by Scimemi (2014a,b) propose the intriguing idea that changes of GABA transporters activity may modulate GABAergic responses. In particular, by exploiting a computer modeling approach, Dr. Scimemi validates the hypothesis that the density, distribution and lateral mobility of GABA transporters affect the GABA concentration sensed by postsynaptic GABAA receptors.

In addition to synaptic inhibition, tonic inhibition produced by the persistent activation of extrasynaptic GABAA receptors is crucial for the tuning of neuronal excitability. Recent evidence demonstrates that also tonic inhibition is plastic. The original article by Barth et al. (2014) illustrates that the ovarian cycle is associated with variations of expression of GABAA receptors containing the “tonic” δ-subunit, both in hippocampal principal cells and interneurons. Interestingly, such plasticity modulates γ-oscillations, thus representing a possible determinant for altered memory and cognitive performance observed during ovarian cycle.

The ability of inhibitory synapses to undergo plasticity emphasized in this ebook raises important questions. First, what are the specific molecular mechanisms of inhibitory plasticity at synapses formed by different interneuron subtypes? Second: how is plasticity orchestrated at both excitatory and inhibitory synapses? In keeping with this, how do different forms of excitatory and inhibitory plasticity co-exist? Do variations of both excitation and inhibition strength occur in parallel/homostatic (Froemke et al., 2007; Xue et al., 2014; Flores et al., 2015), independent (Lourenco et al., 2014), or opposite fashions (Petrini et al., 2014). Are these different “plasticity modes” dependent on the stimulus pattern, specific spatial distributions of synapses and/or time points after plasticity induction? What are the behavioral and cognitive correlates of these different forms of plasticity?

Answering these questions will contribute in redefining the excitation to inhibition balance (E/I) as a “dynamic” activity-dependent determinant for the functioning of brain microcircuits.

## Acknowledgments

This work has been supported by Telethon-Italy (GGP11043) and Compagnia di San Paolo (ROL-4318). Investissements d'avenir" ANR-10IAIHU-06; Agence Nationale de la Recherche (ANR-13-BSV4-0015-01), and a grant from the Institut du Cerveau et de la Moelle épinière (Paris).

## References

* Barth, A. M., Ferando, I., and Mody, I. (2014). Ovarian cycle-linked plasticity of delta-GABAA receptor subunits in hippocampal interneurons affects gamma oscillations *in vivo*. *Front. Cell. Neurosci.* 8:222. doi: 10.3389/fncel.2014.00022

* Chevaleyre, V., and Piskorowski, R. (2014). Modulating excitation through plasticity at inhibitory synapses. *Front. Cell. Neurosci.* 8:93. doi: 10.3389/fncel.2014.00093

* Flores, C. E., Nikonenko, I., Mendez, P., Fritschy, J. M., Tyagarajan, S. K., and Muller, D. (2015). Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation. *Proc. Natl. Acad. Sci. U.S.A.* 112:E65–E72. doi: 10.1073/pnas.1411170112

* Froemke, R. C., Merzenich, M. M., and Schreiner, C. E. (2007). A synaptic memory trace for cortical receptive field plasticity. *Nature* 450:425–429. doi: 10.1038/nature06289

* Gao, Z., van Woerden, G. M., Elgersma, Y., De Zeeuw, C. I., and Hoebeek, F. E. (2014). Distinct roles of alpha- and betaCaMKII in controlling long-term potentiation of GABAA-receptor mediated transmission in murine Purkinje cells. *Front. Cell. Neurosci.* 8:16. doi: 10.3389/fncel.2014.00016

* Griffen, T. C., and Maffei, A. (2014). GABAergic synapses: their plasticity and role in sensory cortex. *Front. Cell. Neurosci.* 8:91. doi: 10.3389/fncel.2014. 00091

* Hirano, T., and Kawaguchi, S.-Y. (2014). Regulation and functional roles of rebound potentiation at cerebellar stellate cell-Purkinje cell synapses. *Front. Cell. Neurosci.* 8:42. doi: 10.3389/fncel.2014.00042

* Houston, C. M., He, Q., and Smart, T. G. (2009). CaMKII phosphorylation of the GABA(A) receptor: receptor subtype- and synapse-specific modulation. *J. Physiol.* 587, 2115–2125. doi: 10.1113/jphysiol.2009.171603

* Iremonger, K. J., Wamsteeker Cusulin, J. I., and Bains, J. S. (2013). Changing the tune: plasticity and adaptation of retrograde signals. *Trends Neurosci.* 36, 471–479. doi: 10.1016/j.tins.2013.04.007

* Kurotani, T., Yamada, K., Yoshimura, Y., Crair, M. C., and Komatsu, Y. (2008). State-dependent bidirectional modification of somatic inhibition in neocortical pyramidal cells. *Neuron* 57, 905–916. doi: 10.1016/j.neuron.2008.01.030

* Lourenco, J., Pacioni, S., Rebola, N., van Woerden, G. M., Marinelli, S., DiGregorio, D., et al. (2014). Non-associative potentiation of perisomatic inhibition alters the temporal coding of neocortical layer 5 pyramidal neurons. *PLoS Biol.* 12:e1001903. doi: 10.1371/journal.pbio.1001903
Luscher, B., Fuchs, T., and Kilpatrick, C. L. (2011). GABAA receptor trafficking-mediated plasticity of inhibitory synapses. *Neuron* 70, 385-409. doi: 10.1016/j.neuron.2011.03.024

Maguire, J. (2014). Stress-induced plasticity of GABAergic inhibition. *Front. Cell. Neurosci.* 8:157. doi: 10.3389/fncel.2014.00157

Mapelli, L., Pagani, M., Garrido, J. A., and D'Angelo, E. (2015). Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit. *Front. Cell. Neurosci.* 9:169. doi: 10.3389/fncel.2015.00169

Mendez, P., and Bacci, A. (2011). Assortment of GABAergic plasticity in the cortical interneuron melting pot. *Neural Plast.* 2011:976856. doi: 10.1155/2011/976856

Muir, J., and Kittler, J. T. (2014). Plasticity of GABAA receptor diffusion dynamics at the axon initial segment. *Front. Cell. Neurosci.* 8:151. doi: 10.3389/fncel.2014.00151

Pallotto, M., and Deprez, F. (2014). Regulation of adult neurogenesis by GABAergic transmission: signaling beyond GABAA-receptors. *Front. Cell. Neurosci.* 8:166. doi: 10.3389/fncel.2014.00166

Petrini, E. M., and Barberis, A. (2014). Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity. *Front. Cell. Neurosci.* 8:300. doi: 10.3389/fncel.2014.00300

Petrini, E. M., Ravasenga, T., Hausrat, T. J., Iurilli, G., Olcese, U., Racine, V., et al. (2014). Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP. *Nat. Commun.* 5:3921. doi: 10.1038/ncomms4921

Raimondo, J. V., Markram, H., and Akerman, C. J. (2012). Short-term ionic plasticity at GABAergic synapses. *Front. Synaptic Neurosci.* 4:5. doi: 10.3389/fnsyn.2012.00005

Scimemi, A. (2014a). Plasticity of GABA transporters: an unconventional route to shape inhibitory synaptic transmission. *Front. Cell. Neurosci.* 8:128. doi: 10.3389/fncel.2014.00128

Scimemi, A. (2014b). Structure, function, and plasticity of GABA transporters. *Front. Cell. Neurosci.* 8:161. doi: 10.3389/fncel.2014.00161

Succol, F., Fiumelli, H., Benfenati, F., Cancedda, L., and Barberis, A. (2012). Intracellular chloride concentration influences the GABAA receptor subunit composition. *Nat. Commun.* 3:738. doi: 10.1038/ncomms1744

Woodin, M. A., Ganguly, K., and Poo, M.-M. (2003). Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl- transporter activity. *Neuron* 39, 807-820. doi: 10.1016/S0896-6273(03)00507-5

Xue, M., Atallah, B. V., and Scanziani, M. (2014). Equalizing excitation-inhibition ratios across visual cortical neurons. *Nature* 511, 596-600. doi: 10.1038/nature13321

Younts, T. J., and Castillo, P. E. (2014). Endogenous cannabinoid signaling at inhibitory interneurons. *Curr. Opin. Neurobiol.* 26, 42-50. doi: 10.1016/j.conb.2013.12.006

Zacchi, P., Antonelli, R., and Cherubini, E. (2014). Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses. *Front. Cell. Neurosci.* 8:103. doi: 10.3389/fncel.2014.00103

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2015 Barberis and Bacci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.