Homeostatic strengthening of inhibitory synapses is mediated by the accumulation of GABA(A) 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: 6.75). 11/2011; 31(48):17701-12. DOI: 10.1523/JNEUROSCI.4476-11.2011
Source: PubMed

ABSTRACT 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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    ABSTRACT: Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE)-derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin-expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability.
    Frontiers in Neural Circuits 09/2012; 6:66. DOI:10.3389/fncir.2012.00066 · 2.95 Impact Factor
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    ABSTRACT: Persistent alterations in network activity trigger compensatory changes in excitation and inhibition that restore neuronal firing rate to an optimal range. One example of such synaptic homeostasis is the downregulation of inhibitory transmission by chronic inactivity, in part through the reduction of vesicular transmitter content. The enzyme glutamic acid decarboxylase 67 (GAD67) is critical for GABA synthesis, but its involvement in homeostatic plasticity is unclear. We explored the role of GAD67 in activity-dependent synaptic plasticity using a mouse line (Gad1(-/-)) in which GAD67 expression is disrupted by genomic insertion of the green fluorescent protein (GFP). Homozygous deletion of Gad1 significantly reduced miniature inhibitory postsynaptic current (mIPSC) amplitudes and GABA levels in cultured hippocampal neurons. The fractional block of mIPSC amplitude by a low affinity, competitive GABA(A) receptor antagonist was higher in GAD67-lacking neurons, suggesting that GABA concentration in the synaptic cleft is lower in knockout animals. Chronic suppression of activity by the application of tetrodotoxin (TTX) reduced mIPSC amplitudes and the levels of GAD67 and GABA. Moreover, TTX reduced GFP levels in interneurons, suggesting that GAD67 gene expression is a key regulatory target of activity. These in vitro experiments were corroborated by in vivo studies in which olfactory deprivation reduced mIPSC amplitudes and GFP levels in glomerular neurons in the olfactory bulb. Importantly, TTX-induced downregulation of mIPSC was attenuated in Gad1(-/-) neurons. Altogether, these findings indicate that activity-driven expression of GAD67 critically controls GABA synthesis and, thus, vesicular filling of the transmitter.
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