Search

Aim We examined if tonic γ‐aminobutyric acid (GABA)‐activated currents in primary hippocampal neurons were modulated by insulin in wild‐type and tg‐APPSwe mice, an Alzheimer’s disease (AD) model. Methods GABA‐activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippocampal brain slices, from 8‐10 weeks old (young) wild‐type mice and in dorsal DG granule cells in adult, 5‐6 and 10‐12 (aged) months old wild‐type and tg‐APPSwe mice, in the absence or presence of insulin, by whole‐cell patch‐clamp electrophysiology. Results In young mice, insulin (1 nM) enhanced the total spontaneous inhibitory postsynaptic current (sIPSCT) density in both dorsal and ventral DG granule cells. The extrasynaptic current density was only increased by insulin in dorsal CA3 pyramidal neurons. In absence of action potentials, insulin enhanced DG granule cells and dorsal CA3 pyramidal neurons miniature IPSCT (mIPSCT) frequency, consistent with insulin regulation of presynaptic GABA release. sIPSCT densities in DG granule cells were similar in wild‐type and tg‐APPSwe mice at 5‐6 months but significantly decreased in aged tg‐APPSwe mice where insulin normalized currents to wild‐type levels. The extrasynaptic current density was increased in tg‐APPSwe mice relative to wild‐type littermates but, only in aged tg‐APPSwe mice did insulin decrease and normalize the current. Conclusion Insulin effects on GABA signalling in hippocampal neurons are selective while multifaceted and context‐based. Not only is the response to insulin related to cell‐type, hippocampal axis‐location, age of animals and disease but also to the subtype of neuronal inhibition involved, synaptic or extrasynaptic GABAA receptors‐activated currents., Hayma Hammoud and Olga Netsyk are co‐first authors and contributed equally.Sergiy V. Korol and Zhe Jin contributed equally.

The hippocampus is a medial temporal lobe structure in the brain and is widely studied for its role in memory and learning, in particular, spacial memory and emotional responses. It was thought to be a homogenous structure but emerging evidence shows differentiation along the dorsoventral axis and even microdomains for functional and cellular markers. We have examined in two cell‐types of the hippocampal projection neurons, the dentate gyrus (DG) granule cells and CA3 pyramidal neurons, if the GABA‐activated tonic current density varied between the dorsal (septal) and the ventral (temporal) poles of the male mouse hippocampus. Tonic synaptic currents, arising from spontaneous and miniature inhibitory postsynaptic currents (sIPSC, mIPSC), and extrasynaptic tonic currents were evaluated. The results revealed different levels of sIPSC but not mIPSC density between the dorsal and ventral hippocampal neurons for both the DG granule cells and the CA3 pyramidal neurons. The extrasynaptic tonic current density was larger in the DG granule cells as compared to the CA3 pyramidal neurons but did not vary between the dorsal and ventral regions. IPSC bursting was observed in both cell‐types in the ventral hippocampus but was more common in the CA3 pyramidal neurons. Only in the dorsal DG granule cells was the level of the sIPSC and mIPSC density similar. The results indicate that the tonic GABAergic inhibition is particularly strong in the ventral hippocampal DG granule cells and enhanced in the dorsal as compared to the ventral hippocampal CA3 pyramidal neurons.