GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation

Abstract

The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The extent of LTP impairment depended on the precise burst frequency, with significant impairment at 3-7 Hz that correlated with the time course of elevated GABAergic inhibition caused by GAT1 disruption. Furthermore, in vivo electrophysiological recordings showed that GAT1 gene deletion reduced the frequency of hippocampal theta oscillation. Moreover, behavioral studies showed that GAT1 knock-out mice also exhibited impaired hippocampus-dependent learning and memory. Together, these results have highlighted the important link between GABAergic inhibition and hippocampal theta oscillation, both of which are critical for synaptic plasticity and learning behaviors.

Enhanced learning and memory in <italic>GAT1</italic> heterozygous mice

“…Chronically elevated GABA levels also downregulated phasic GABA release and reduced presynaptic signaling via GABA B receptors, thus causing an enhanced tonic and a diminished phasic inhibition [36]. In a previous study using the same strain of GAT1 2/2 mice as used in our current research, Gong et al [18] demonstrated that GAT1 disruption specifically impaired TBS-induced LTP. They showed that GAT1 disruption specifically altered the temporal pattern of hippocampal theta oscillations by reducing the oscillation frequency, and these specific changes in the theta network activity and synaptic plasticity were accompanied by severe impairment of hippocampus-dependent learning and memory.…”

“…However, mild changes were found in some genes involved in GABAergic and glutamatergic transmission, synaptic plasticity, and cognitive formation. Other evidences also indicated that neither genes expression nor synaptic structure changed significantly in the hippocampus of GAT1 knockout mice [18,36]. These data indicate that behavioral and electrophysiological changes in GAT1 þ/2 mice may mainly depend on the process of neurotransmision.…”

“…GABA reuptake via GAT1 is essential for modulating the rhythm of theta activity, GAT1 activity does not affect the physiological expression of theta oscillation activity, but modulates the precise frequency of this oscillation [18]. In wild-type mice, the time course of GABA release and reuptake cycle which present a bell-shaped effect generates a moderate inhibition at subsequent excitatory action.…”

“…However, uptake activity is dramatically reduced to near baseline in GAT1 knockout mice (GAT1 2/2 ) [17]. Our previous study showed that homozygous GAT1 2/2 mice exhibited impaired hippocampusdependent learning and memory [18]. We also found that overexpression of GAT1 led to cognitive deterioration in transgenic mice [19].…”

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

“…Dendritic spines were also vGLUT1 positive, indicating that spines were receptive to glutamatergic signaling. Interestingly, there were fewer vGLUT1-positive spines compared with synapsin1-positive spines, suggesting that some synapses may be involved in nonglutamatergic neurotransmitter pathways, which are also known to play an important role in learning and memory processing (Jerusalinsky et al, 1997;Gong et al, 2009). Fig.…”