Homeostatic Strengthening of Inhibitory Synapses Is Mediated by the Accumulation of GABAA Receptors

Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia 22908, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2011; 31(48):17701-12. DOI: 10.1523/JNEUROSCI.4476-11.2011
Source: PubMed


Mechanisms of homeostatic plasticity scale synaptic strength according to changes in overall activity to maintain stability in neuronal network function. This study investigated mechanisms of GABAergic homeostatic plasticity. Cultured neurons exposed to depolarizing conditions reacted with an increased firing rate (high activity, HA) that normalized to control levels after 48 h of treatment. HA-treated hippocampal neurons displayed an attenuated response to further changes in depolarization, and the firing rate in HA-treated neurons increased above normalized levels when inhibition was partially reduced back to the level of control neurons. The amplitude and frequency of mIPSCs in hippocampal neurons increased after 48 h of HA, and increases in the size of GABA(A) receptor γ2 subunit clusters and presynaptic GAD-65 puncta were observed. Investigation of the time course of inhibitory homeostasis suggested that accumulation of GABA(A) receptors preceded presynaptic increases in GAD-65 puncta size. Interestingly, the size of GABA(A) receptor γ2 subunit clusters that colocalized with GAD-65 were larger at 12 h, coinciding in time with the increase found in mIPSC amplitude. The rate of internalization of GABA(A) receptors, a process involved in regulating the surface expression of inhibitory receptors, was slower in HA-treated neurons. These data also suggest that increased receptor expression was consolidated with presynaptic changes. HA induced an increase in postsynaptic GABA(A) receptors through a decrease in the rate of internalization, leading to larger synaptically localized receptor clusters that increased GABAergic synaptic strength and contributed to the homeostatic stabilization of neuronal firing rate.

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    • "Previous results have reported that the hyperexcitationinduced homeostatic plasticity would result from a synaptic downscaling occurring at both excitatory (Chang et al, 2010; Goold and Nicoll, 2010) and inhibitory synapses (Hartmann et al, 2008; Rannals and Kapur, 2011). Although several mechanisms might be at the basis of such complex event, we concentrated our study on the downregulation of the VGNa þ channel-mediated intrinsic excitability of excitatory "
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    ABSTRACT: Intrinsic homeostasis enables neuronal circuits to maintain activity levels within an appropriate range by modulating neuronal voltage-gated conductances, but the signalling pathways involved in this process are largely unknown. We characterized the process of intrinsic homeostasis induced by sustained electrical activity in cultured hippocampal neurons based on the activation of the Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). We showed that 4-aminopyridine-induced hyperactivity enhances the expression of REST/NRSF, which in turn, reduces the expression of voltage-gated Na(+) channels, thereby decreasing the neuronal Na(+) current density. This mechanism plays an important role in the downregulation of the firing activity at the single-cell level, re-establishing a physiological spiking activity in the entire neuronal network. Conversely, interfering with REST/NRSF expression impaired this homeostatic response. Our results identify REST/NRSF as a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network.
    The EMBO Journal 10/2013; 32(22). DOI:10.1038/emboj.2013.231 · 10.43 Impact Factor
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    • "The concurrent increase in the density of short-lived boutons suggests increased axonal transport and exchange between neighboring inhibitory synapses, possibly reflecting increased competition for limited (presynaptic) resources (Govindarajan et al., 2011; Ratnayaka et al., 2011). We propose that the rapid adjustment of bouton dynamics and exchange of bouton content along the inhibitory axon during changes in network activity could serve to facilitate presynaptic changes (Hartman et al., 2006; Peng et al., 2010; Rannals and Kapur, 2011; Kuriu et al., 2012). When more presynaptic material would become available over time [e.g. by increased protein synthesis (Huang and Scheiffele, 2008)], an increased demand for presynaptic resources could lead to an overall strengthening of synapses. "
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    ABSTRACT: Coordinated changes at excitatory and inhibitory synapses are essential for normal brain development and function. It is well established that excitatory neurons undergo structural changes, but our knowledge about inhibitory structural plasticity is rather scarce. Here we present a quantitative analysis of the dynamics of GABAergic boutons in the dendritic region of the hippocampal CA1 area using time-lapse two-photon imaging in organotypic hippocampal cultures from GAD65-GFP mice. We show that ~20% of inhibitory boutons are not stable. They are appearing, disappearing and reappearing at specific locations along the inhibitory axon and reflect immature or incomplete synapses. Furthermore, we observed that persistent boutons show large volume fluctuations over several hours, suggesting that presynaptic content of inhibitory synapses is not constant. Our data show that inhibitory boutons are highly dynamic structures and suggest that inhibitory axons are continuously probing potential locations for inhibitory synapse formation by redistributing presynaptic material along the axon. In addition, we found that neuronal activity affects the exploratory dynamics of inhibitory axons. Blocking network activity rapidly reduces the number of transient boutons, whereas enhancing activity reduces the number of persistent inhibitory boutons, possibly reflecting enhanced competition between boutons along the axon. The latter effect requires signaling through GABAA receptors. We propose that activity-dependent regulation of bouton dynamics contributes to inhibitory synaptic plasticity.
    Frontiers in Neural Circuits 06/2013; 7:113. DOI:10.3389/fncir.2013.00113 · 3.60 Impact Factor
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    • "GABARAPL1 has also been shown to bind to and is potentially implicated in trafficking of the GABAAR (gamma-aminobutyric acid type A receptor) [22]. Regulation of GABAAR numbers and clustering is important for modulation of synaptic strength at inhibitory synapses, which is mediated by an accumulation of the GABAAR at the postsynaptic dendrite to maintain neural network homeostasis [35]. Given that GABARAPL1 interacts with this receptor and is expressed in GABAergic neurons, it may also play a role for in neural network homeostasis. "
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    ABSTRACT: Macroautophagy is a highly conserved cellular degradation process, regulated by autophagy-related (atg) factors, in which a double membrane autophagosome engulfs cytoplasmic components to target them for degradation. In yeast, the Atg8 protein is indispensable for autophagosome formation. In mammals, this is complicated by the presence of six Atg8 homologues grouped into the GABARAP and MAP1LC3 subfamilies. Although these proteins share a high similarity, their transcript expression, regulation and protein interactions differ, suggesting they may display individual properties and specific functions. GABARAPL1/GEC1 is a member of the GABARAP subfamily and its mRNA is the most highly expressed Atg8 homologue in the central nervous system. Consequently, we performed an in depth study of GABARAPL1 distribution in the developing and adult murine brain. Our results show that GABARAPL1 brain expression is visible as early as embryonic day 11 and progressively increases to a maximum level in the adult. Immunohistochemical staining was detected in both fibers and immature neurons in embryos but was restrained to neurons in adult tissue. By E17, intense punctate-like structures were visible and these accumulated in cortical primary neurons treated with the autophagosome/lysosome fusion inhibitor Bafilomycin A1 (Baf A1), suggesting that they represent autophagosomes. Finally, GABARAPL1 expression was particularly intense in motoneurons in the embryo and in neurons involved in somatomotor and neuroendocrine functions in the adult, particularly in the substantia nigra pars compacta, a region affected in Parkinson's disease. Our study of cerebral GABARAPL1 protein expression provides insight into its role in the development and homeostasis of the mouse brain.
    PLoS ONE 05/2013; 8(5):e63133. DOI:10.1371/journal.pone.0063133 · 3.23 Impact Factor
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