Activity-Dependent Response Reduction of GABAA Receptors in Major Depressive Disorder
Limon A, Mamdani F, Vawter M, Lee FS, Schatzberg AF, Myers RM, Barchas JD, Akil H, Watson SJ, Bunney WE, Sequiera A
American College of Neuropsychopharmacology. 2017.
Background: Major depressive disorder (MDD) is a leading cause of disability worldwide characterized by altered neuronal activity and abnormal excitability in brain regions involved in the control of stress and emotion. Transcriptional alterations of inhibitory GABA receptors have been found in postmortem brain samples of the dorsolateral prefrontal cortex (DLPFC) from individuals with MDD. The functional consequences of these alterations are unknown because of the lack of GABA specific ion flux measurements in human membranes. To address this problem, we optimized a novel approach to directly measure ion currents from synaptic GABA receptors isolated from postmortem brains of subjects with MDD to contrast with controls. We show in our preliminary work that GABA-A receptors become less efficient upon repetitive stimulation in the DLPFC of subjects with MDD compared to controls.
Methods: We microtransplanted human synaptic membranes containing native GABA receptors, from the postmortem DLPFC of 16 controls and 22 MDD subjects, into Xenopus oocytes. The oocyte membrane provides a functional platform for the direct electrophysiological characterization of native human synaptic receptors. Ion currents through GABA receptors were used to determine the maximum amplitude of the responses, their kinetic properties and the decay of the current amplitude upon repeated stimulation. Excitatory AMPA receptors present in the same preparations were also recorded with 100 μM kainate to calculate the electrophysiological excitation to inhibition ratio (E/I). All electrophysiological parameters were determined for each subject.
Results: Functional responses of native GABA receptors in controls and MDDs were similar in maximum amplitude, activation time and desensitization (P 4 0.05, two tailed t-tests). No effects of postmortem interval, RIN, gender or pH were observed for these parameters on functional responses of GABA receptors. There was a trend for an association between age and maximum GABA current (r (38) = 0.32; P = 0.056). Responses to kainate were similar between MDD cases and controls (P 4 0.05), consequently, the E/I ratio was not different between groups. Interestingly, repetitive application of GABA elicited a differential rundown of GABA receptor currents between control and MDD cases. To facilitate the comparison with other in vitro studies, GABA current rundown was defined as the decrease of the peak current amplitude after six consecutive applications of GABA,10 s duration and 40 s interval between applications (Ragozzino et al., 2005; PNAS, 102: 15219). The response to the 6th application was reduced to 42 ± 7 % in control vs 34 ± 8 % in MDD (Mean ± SD, P = 0.006, two tailed t-tests) compared to the first application. Comparison between MDD who did not commit suicide (n =14) and MDD cases who committed suicide (n = 8) shows similar rundown (35 ± 7 % in MDD vs 34 ± 10 in MDD-suicide).
Conclusions: Our results show that synaptic GABA receptors from the DLPFC of MDD cases have significantly smaller responses after repeated stimulation compared to controls, suggesting that in conditions of high synaptic demand (e.g. stress) GABAergic signaling responsivity might be compromised and the inhibitory/excitatory balance lost in MDD. Potential pro-excitatory alterations caused by enhanced rundown of GABA receptors may underline a statedependent abnormal excitability in the DLPFC of individuals with MDD. These results if confirmed should point to novel pharmacological targets aiming to modulate GABA responsivity in MDD.