Electrophysiological evaluation of extracellular spermine and alkaline pH on synaptic human GABA A receptors

• Published in: Translational psychiatry Vol. 9; no. 1; p. 218
• Main Authors: Limon, A, Delbruck, E, Yassine, A, Pandya, D, Myers, R M, Barchas, J D, Lee, F, Schatzberg, Watson, S J, Akil, H, Bunney, W E, Vawter, M P, Sequeira, A
• Format: Journal Article
• Language: English
• Published: United States 05-09-2019
• Subjects: Humans; Hydrogen-Ion Concentration; Neurons - drug effects; Neurons - metabolism; Oocytes - drug effects; Oocytes - metabolism; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Receptors, GABA-A - metabolism; Spermine - pharmacology; Synapses - drug effects; Synapses - metabolism; Synaptic Membranes - drug effects; Synaptic Membranes - metabolism
• ISSN: 2158-3188
• DOI: 10.1038/s41398-019-0551-1

Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABA
receptors (GABA
Rs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABA
Rs, has on human postmortem native GABA
Rs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABA
Rs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABA
Rs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABA
Rs, spermine-mediated shifts of pH inhibit GABA
Rs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.