Diabetes induces a number of neurological changes that may render the hippocampus more susceptible to age-related structural and functional deficits. In hippocampal slices from diabetic and non-diabetic animals, application of the MR agonist aldosterone restored LTP at medial perforant path – dentate gyrus synapses, implicating this receptor population in corticosterone-mediated learning impairments (Stranahan et al., 2008
). We have also replicated and extended previous studies demonstrating impairment of dentate gyrus LTP in STZ diabetic animals (Kamal et al., 1999
; Stranahan et al., 2008
). Our observation of a change in the threshold for LTD suggests that bidirectional synaptic plasticity may also be altered at medial perforant path synapses in the diabetic brain.
The effect of diabetes on bidirectional synaptic plasticity in the dentate gyrus is similar, but not identical to the literature on diabetes-induced regulation of Schaffer collateral LTD in hippocampal area CA1. A previously published study has shown that insulin deficient rats exhibit reduced LTP and enhanced LTD at Schaffer collateral-CA1 synapses (Kamal et al., 1999
). However, we have observed reduced LTP, and a bias in favor of LTD following intermediate stimulus frequencies (5 and 10 Hz) in the dentate gyrus. We did not observe any differences in the magnitude of LTD following 900 pulses at 1 Hz. One possible explanation for this difference involves adult neurogenesis, which occurs throughout life in the dentate gyrus, but not in CA1. The number of adult-generated neurons is reduced in STZ-diabetic animals (Stranahan et al., 2008
). Because newly generated neurons show increased excitability and lower thresholds for LTP induction (Schmidt-Hieber et al., 2004
), it is possible that a reduction in their number could influence the threshold for LTP and LTD in the dentate gyrus. Taking into consideration the fact that these experiments were conducted in the presence of the GABAA receptor antagonist picrotoxin, which silences GABAergic excitation among new neurons during the first week after their birth (Ge et al., 2006
), it is tempting to speculate that the current results might be due to reductions in the number of adult-generated neurons that reach maturity. Even after new neurons transition from GABAergic excitation to glutamatergic excitation, they retain greater morphological plasticity (Zhao et al., 2006
), and the loss of this population could have an impact on synaptic plasticity.
In diabetic humans, pharmacological treatments that alter the availability of corticosterone can improve cognition (Sandeep et al., 2004
). It remains to be seen whether central activation of MR alters cognition in individuals with diabetes. We have observed that aldosterone restores LTP at medial perforant path synapses on dentate granule neurons in diabetic animals. Future studies will be necessary to fully characterize the role of the MR system in diabetes models, and in models of chronic stress. Understanding the overlap between the mechanisms of diabetes and anxiety could help to develop population-specific treatment for individuals suffering from both disorders.