Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C085

Oral Communications

Effect of insulin on GABAergic signalling in hippocampal dentate gyrus granule cells in a mouse model of Alzheimer's disease

O. Netsyk1, Z. Jin1, S. V. Korol1, H. Hammoud1, A. Tafreshiha1, J. Li2, B. Birnir1

1. Department of Neuroscience, Uppsala University, Uppsala, Sweden. 2. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

Epidemiological data suggest that altered insulin signalling can increase the propensity for the development of cognitive decline & progression of Alzheimer's disease (AD) in humans. Also, peripheral glucose & insulin resistance was reported in several mouse models of AD after 9 months (1). The dentate gyrus (DG) is the principal gateway of cortical input to the hippocampus (2) & plays an important role for the formation & recall of memory. It has been shown that the DG region is one of the first & where most plaques are deposited both in AD mouse models & in the brains of humans with AD (3). Also, patients with AD show elevated inhibitory neurotransmitter GABA levels in the cerebrospinal fluid. It has been hypothesized that an abnormal increase in GABAergic tonic conductance in the hippocampus may, in part, underlie the memory impairment in AD (4). As insulin & insulin sensitizers can improve cognitive function in AD (1, 4), we examined the effect of physiological concentrations of insulin on GABAergic signalling in DG granule cells (GCs) in aged wild type (WT) & transgenic (tgSwe) mice overexpressing betaAPP with Swedish mutation (5). Aged (10-12 months old) male & female tgSwe & C57BL6 WT mice were euthanized by cervical dislocation procedure. Whole-cell patch-clamp recordings were performed on DG GCs from dorsal hippocampal slices (350μm thick). Patched neurons were filled with neurobiotin for further 3D reconstruction. Neuritic plaques were detected by Thioflavin S stain. Values are means±S.E.M., compared by two-tailed Student's t-test. The phasic & tonic GABAergic currents were recorded in GCs of dorsal hippocampus in aged WT & tgSwe mice. The frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) recorded from GCs were similar in WT & tgSwe mice. However, the GABA-evoked tonic current amplitude was significantly higher in GCs of DG of tgSwe mice compared to the WT mice (9.2±1.3pA n=12 vs 4.2±1.3pA, n=6, p<0.01, respectively) & was partially suppressed by selective inverse agonist for the GABAA receptors containing α5 subunit L-655,708 (100nM) by 36±16%, n=3. Further, we pre-incubated slices with insulin (1 nM) & then measured the GABA-activated tonic current amplitude in DG neurons in WT control (4.2±0.5pA, n=6) & compared with the amplitude obtained in tgSwe mice (7.2±2.2pA, n=10) but the results were, on the average, similar (p>0.05). sIPSCs of GCs were not modulated by insulin in old WT mice. The frequency of sIPSCs in tgSwe mice was significantly higher in the presence of insulin compared to control condition (0.9±0.1Hz, n=10 vs 0.6±0.1Hz, n=9, p<0.05, respectively). Thus, the data suggest that GABA-activated tonic inhibitory current in DG neurons is increased in tgSwe mice. Insulin at physiological concentrations modulates GABAergic signalling in AD mouse model.

Where applicable, experiments conform with Society ethical requirements