Insulin and its receptor are both present in the central nervous system and are implicated in neuronal survival and hippocampal synaptic plasticity. Here we show that insulin activates phosphatidylinositol 3‐kinase (PI3K) and protein kinase B (PKB), and results in an induction of long‐term depression (LTD) in hippocampal CA1 neurones. Evaluation of the frequency–response curve of synaptic plasticity revealed that insulin induced LTD at 0.033 Hz and LTP at 10 Hz, whereas in the absence of insulin, 1 Hz induced LTD and 100 Hz induced LTP. LTD induction in the presence of insulin required low frequency synaptic stimulation (0.033 Hz) and blockade of GABAergic transmission. The LTD or LTP induced in the presence of insulin was N‐methyl‐d‐aspartate (NMDA) receptor specific as it could be inhibited by α‐amino‐5‐phosphonopentanoic acid (APV), a specific NMDA receptor antagonist. LTD induction was also facilitated by lowering the extracellular Mg²⁺ concentration, indicating an involvement of NMDA receptors. Inhibition of PI3K signalling or discontinuing synaptic stimulation also prevented this LTD. These results show that insulin modulates activity‐dependent synaptic plasticity, which requires activation of NMDA receptors and the PI3K pathway. The results obtained provide a mechanistic link between insulin and synaptic plasticity, and explain how insulin functions as a neuromodulator.

Moderate impairment of learning and memory has been recognized as a complication of diabetes. The present study examined behavioral and electrophysiological measures of cerebral function in streptozotocin (STZ)-induced diabetic rats. Behavioral testing consisted of a spatial learning task in a water maze. Electrophysiological testing consisted of in vitro assessment of hippocampal long-term potentiation (LTP), an activity-dependent form of synaptic plasticity, which is believed to be related to the cellular mechanisms of learning and memory. Two experiments were performed: the first with severely hyperglycemic rats and the second with moderately hyperglycemic rats. Rats were tested in the water maze 11 weeks after induction of diabetes. Next, LTP was measured in vitro in trained animals. Both spatial learning and LTP expression in the CA1 field of the hippocampus were impaired in severely hyperglycemic rats as compared with nondiabetic controls. In contrast, spatial learning and hippocampal LTP were unaffected in moderately hyperglycemic rats. The association of alterations in hippocampal LTP with specific learning impairments has previously been reported in conditions other than diabetes. Our findings suggest that changes in LTP-like forms of synaptic plasticity in the hippocampus, and possibly in other cerebral structures, are involved in learning deficits in STZ-induced diabetes. The beneficial effect of moderate glycemic control on both place learning and hippocampal LTP supports the significance of the relation between these two parameters and indicates that the development of the observed deficits may be related to the level of glycemic control.