Activity Deprivation Reduces Miniature IPSC Amplitude by Decreasing the Number of Postsynaptic GABA_AReceptors Clustered at Neocortical Synapses

Abstract

Maintaining the proper balance between excitation and inhibition is necessary to prevent cortical circuits from either falling silent or generating epileptiform activity. One mechanism through which cortical networks maintain this balance is through the activity-dependent regulation of inhibition, but whether this is achieved primarily through changes in synapse number or synaptic strength is not clear. Previously, we found that 2 d of activity deprivation increased the amplitude of miniature EPSCs (mEPSCs) onto cultured visual cortical pyramidal neurons. Here we find that this same manipulation decreases the amplitude of mIPSCs. This occurs with no change in single-channel conductance but is accompanied by a reduction in the average number of channels open during the mIPSC peak and a reduction in the intensity of staining for GABA(A) receptors (GABA(A)Rs) at postsynaptic sites. In addition, the number of synaptic sites that express detectable levels of GABA(A)Rs was decreased by approximately 50% after activity blockade, although there was no reduction in the total number of presynaptic contacts. These data suggest that activity deprivation reduces cortical inhibition by reducing both the number of GABA(A)Rs clustered at synaptic sites and the number of functional inhibitory synapses. Because excitatory and inhibitory synaptic currents are regulated in opposite directions by activity blockade, these data suggest that the balance between excitation and inhibition is dynamically regulated by ongoing activity.

Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor

“…In support, previous evidence demonstrated that variations in both the GABA content of vesicles (Frerking et al, 1995) and the number of postsynaptic GABA A receptors (Nusser et al, 1997(Nusser et al, , 1998 determine mIPSC amplitude. Moreover, a reduction in both the staining intensity of GAD-65 and synaptic GABA A receptors was previously observed in cultured cortical neurons after activity blockade (Kilman et al, 2002).…”

“…Neuronal activity can also regulate the strength of inhibitory synapses (Kilman et al, 2002), although the signals that mediate this process are unknown. Similar to excitatory synapses, BDNF is an attractive candidate to scale the strength of inhibitory synapses in response to long-term alterations in neuronal activity.…”

Consequences of unilateral hearing loss: Cortical adjustment to unilateral deprivation

“…Most importantly, they demonstrate that conductive impairment at a very early age may induce re-organization within auditory cortex, where CHL occurring later in development may promote a different mode or temporal sequence of cortical re-organization. These different modes may include potential plastic changes (e.g., Irvine, 2007) or perturbed expression of neurotransmitters or their receptors (e.g., Cherubini et al, 1991;Gao et al, 1999;Kilman et al, 2002;Yu et al, 2006). Regardless of the underlying mechanism, our main observation remains that in response to low frequency sound stimulation, CHL, but not CA, decreases activity in auditory cortex.…”

Time scales of memory, learning, and plasticity

“…Only a few experimental studies have been done on inhibitory plasticity (Kilman et al 2002;Woodin et al 2003;Haas et al 2006;Wenner 2011), and theoretical modeling is almost nonexistent (Vogels et al 2011). It would be important to study the advantages and possibilities of inhibition so that more links to memory and learning could be made.…”