Tonic GABA‐activated synaptic and extrasynaptic currents in dentate gyrus granule cells and CA3 pyramidal neurons along the mouse hippocampal dorsoventral axis

Abstract

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.

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease

“…The sIPCSs rise‐time was faster in the ventral hippocampus in the presence of insulin but no effect was recorded on the current decay (Figure A). As the DG granule cells at the two hippocampal poles vary in size, 29 we calculated the sIPSC density. Insulin increased the mean sIPSC density by ~54% and ~22% in the dorsal and ventral DG granule cells, respectively (Figure 2E).…”

“…However, in the dorsal DG granule cells from tg‐APPSwe mice, the insulin modulation was related to age and progression of the disease (Figure 10B). The results indicate that insulin regulates GABA signalling when neuronal networks are changing, as happens during maturation of the young brain 3,29 and as the disease progresses in the hippocampus of the aged tg‐APPSwe mice 38,62 …”

“…A number of different mechanisms have been proposed to explain the observed higher excitability of the ventral hippocampus, including reduced inhibitory GABAergic tone 53 . We recently showed, in eight to ten weeks old wild‐type mice, that characteristic tonic GABA‐activated currents are recorded in hippocampal primary neurons according to the cell‐type and the dorsoventral hippocampal‐axis location 29 . Here, we examined if insulin modulates tonic GABA‐activated conductance in DG granule cells and CA3 pyramidal neurons in dorsal and ventral hippocampus of young, eight to ten weeks old wild‐type mice and then, in DG granule cells, if the insulin modulation was intact in older wild‐type and tg‐APPSwe mice, before and during amyloid plaques formation.…”

“…The receptors mediate functionally distinct types of inhibition: the fast point‐to‐point synaptic transmission is mediated by high concentrations (millimolar) of GABA, activating synaptic GABA A receptors, whereas the extrasynaptic GABA A receptors are activated by low micro to sub‐micromolar GABA concentrations or spontaneously opening channels, and mediate a persistent form of inhibition. The GABA‐activated inhibitory currents in a neuron then result from the summation of inhibitory postsynaptic currents 25‐29 and from extrasynaptic GABA A receptors currents 29‐36 . Synaptic currents activated by spontaneous firing of interneurons are termed sIPSCs and the action‐potential independent currents, mIPSCs 25‐29 …”

“…Electrophysiological properties of hippocampal neurons along the hippocampal longitudinal axis vary 29,45‐50 and there appears to be increasing neuronal excitability from the dorsal to the ventral pole of the hippocampus 47,49,51‐54 . A number of different mechanisms have been proposed to explain the observed higher excitability of the ventral hippocampus, including reduced inhibitory GABAergic tone 53 .…”