Attenuation of mGluR1/5-dependent synaptic plasticity and ERK pathway dysfunction in the hippocampus of diabetic rats

Streptozotocin-induced diabetic rats (STZ rats), an established animal model of type 1 diabetes mellitus, develop cognitive decline, which has been linked to impairments in hippocampal synaptic plasticity. Long-term depression (LTD) in the hippocampus may be induced by the activation of different types of G protein-coupled receptors, particularly metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors. We previously demonstrated that acetylcholine receptor activation-dependent LTD was impaired in STZ rats, and herein investigated group I mGluR (mGluR1/5)-dependent LTD in the Schaffer collateral-CA1 synapses of STZ rats. Extracellular field recordings revealed that the chemical activation of mGluR1/5 with (S)-3,5-dihydroxyphenylglycine (DHPG, 50 μM, 10 min) induced sustained LTD in both control and STZ rats; however, the magnitude of DHPG-LTD was significantly smaller in STZ rats. Moreover, the paired-pulse ratio between before and 80 min after the application of DHPG increased in both control and STZ rats, and DHPG-LTD was independent of NMDA receptor activation. A Western blot analysis showed that DHPG-induced extracellular signal-regulated kinase (ERK) phosphorylation was reduced in STZ rats, whereas DHPG-induced phosphoinositide-dependent kinase 1 phosphorylation and the expression level of the scaffold protein, Homer1, were unchanged. Collectively, these results suggest that impaired ERK/MAPK signaling affected hippocampal mGluR1/5-dependent LTD in STZ rats, and the dysregulation of ERK may contribute to diabetes-associated cognitive decline because of its crucial role in protein synthesis-dependent synaptic plasticity.