Blockade Of The GABA Transporter Enhances Synchronous Activity Of Interneurons In Hippocampal CA1

One of the main representations of rodents' hippocampus is different oscillations of local field potential under different behavioral states.These activities of the network in brain are closely related to learning and memory.In recent years,more evidence has shown that interneurons may play an important role in regulation of local field potential in the hippocampal CA1 areas.In the Central Nervous System, most of interneurons are the GABAergic neurons.GABA transporter(GAT-1) is a key part in GABA uptake.After GAT-1 being blocked,GABA concentration in synaptic cleft will be raised.In the experiment,we use GAT-1 knockout mice and wild type mice,exploring the influence on the firing patterns of hippocampal CA1 interneurons and oscillations of local field potentials through multi-channel recording techniques in vivo.Recorded during exploration,wild type mouse has shown a clear theta rhythm in hippocampal CA1 area,theta wave peak frequency is at 8.08±0.57 Hz.It did not show any dominant theta frequency during slow-wave sleep.The main findings in our study show that there is a low-frequency theta oscillations which is behaviour independent in GAT-1 knockout mice.Theta peak frequency is at 5.90±0.04 Hz during exploration.The peak frequency of theta is at 5.04±0.04 Hz during the slow-wave sleep.Further study on the function of GAT-1 deficiency,we use the GAT-1-selective inhibitor tiagabine(TGB).Our results indicate that a stable low-frequency theta rhythm can be induced by TGB,and the peak frequency is 3.87±0.06 Hz.The results show that a low frequency oscillation in the theta frequency range is induced by an increase of GABA concentrations into the synaptic cleft.This theta frequency was not affected by behavioral state.Neuronal activity patterns were further analyzed.One is burst-discharge patterns interneurons,the other is ripple-associated interneurons.GAT-1 deficiency leads to enhanced extracellular GABA level and results in decrease in fire frequency in the hippocampal interneurons.During the exploration,the average frequency of burst-discharge pattern interneurons is 30.97±1.50 Hz in wild type mouse.But it is 17.60±1.54 Hz in GAT-1 knockout mouse.Injection of TGB in the wild type mouse,it is 8.95±1.86 Hz.Our study shows similar results in ripple-associated interneurons.Meanwhile,GABA-level increasing in synaptic cleft also can change the firing patterns of the interneurons.It may enhance synchronization of firing patterns.During both exploration and slow -wave sleep states,compared with that of wild type,the firing synchronization can be enhanced by GAT-1 blockade.Furthermore,GABA-level increasing in synaptic cleft,burst-discharge pattern interneurons fire with 5.32±0.14Hz in periodic during exploration and with 5.32±0.14Hz in periodic during slow -wave sleep.By injection of TGB,the periodicity is 3.33±0.06Hz.The ripple-associated interneurons fire phase-locked to theta oscillation in wild-type mice.The experimental data shows that ripple-associated interneurons fires at irregular in GAT-1 knockout mouse.After injection TGB drug, the periodicity is disappears completely.The results suggest that GABA-level increasing promotes synchronized in hippocampal interneurons.Synchronization of burst-discharge pattern interneurons has a high relation to the emergence of low-frequency theta oscillation during increasing GABA levels in hippocampus.