α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Abstract

Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABA A R)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABA A R subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by ␣5 subunit-containing GABA A Rs (␣5GABA A Rs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the ␣5 subunit of the GABA A R (Gabra5 ؊/؊ mice). In addition, the strength of fearassociated memory was studied. The results showed that ␣5GABA A R activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10 -20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of ␣5GABA A Rs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by ␣5GABA A Rs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, ␣5GABA A R activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticity in vitro and certain forms of memory in vivo.

Sustained increase in α5GABAA receptor function impairs memory after anesthesia

“…Since glial-neuron interactions might contribute to the increase in tonic current observed in ex vivo slices, neuronglia cocultures were treated with etomidate. Etomidate did not to changes in synaptic and extrasynaptic GABA A R activity (16,17). Twenty-four hours after treatment, the potentiation of field postsynaptic potentials (fPSPs) was significantly lower in slices from etomidate-treated mice (60 minutes after stimulation; Figure 1C).…”

“…The Schaffer collateral pathway was stimulated at a threshold frequency (20 Hz) that induces synaptic potentiation (16). Under these conditions, synaptic plasticity is sensitive Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months.…”

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…These inhibitory receptors can thus mediate an inhibitory chloride current that controls the baseline firing threshold of pyramidal neurons 44. Tonic or extrasynaptic GABA signaling is a target in the learning and memory field, as blocking this current promotes neuronal excitability in the hippocampus and enhances learning and memory in many animal models 44, 45, 46. In stroke, tonic GABA signaling is increased in peri‐infarct cortex in a zone of cortex near the stroke site (0.2mm adjacent to the stroke) and produces a hypoexcitable state in pyramidal neurons in brain regions that normally mediate recovery of function.…”

Inhibition of learning and memory by general anesthetics

“…In particular, a5 subunit-containing GABA A receptors (a5GABA A receptors) are predominantly expressed in the hippocampus where they are critically involved in physiological learning and memory processes. 143 Anesthetics appear to ''superactivate'' the a5GABA A receptor and ''highjack'' the normal memory-regulating physiological functions, thereby causing profound inhibition and memory blockade (Fig. 4A).…”