Disorganized hippocampal excitatory and inhibitory connectivity in a mouse model of Alzheimer's disease.

Cortical hyperexcitability is regarded to accompany Alzheimer's disease (AD) and its rodent models, and often claimed to be even causative of AD. To seek its morphological backgrounds, spatial learning was assessed with the Morris water maze test (MWM) in male 3xTg Alzheimer's model mice of 5-6 months old, then their hippocampal tissue was examined by electron microscopy (EM). By assigning EM-based asymmetric and symmetric synapses to excitatory (E) and inhibitory (I) synapses, respectively, and by attributing synapses on spines to those onto excitatory (E) postsynaptic neurons, we defined 2 different types of synapses: E-to-E and I-to-E synapses. In addition, synapses onto non-spinous structures (N) of postsynaptic neurons were designated as E-to-N or I-to-N. We thus categorized hippocampal synapses into 4 classes. I-to-E synapses were 7-fold denser in 3xTg than in wild-type mice, whereas the other types did not differ in density. In MWM, there was a non-significant tendency that AD mice perform worse than WT mice. We found a non-significant tendency for the E-to-E synapse density to correlate inversely with MWM performance in AD mice, though the correlation was significant with AD and WT mice pooled together. When E-to-E and E-to-N synapses are combined as the asymmetric synapse class, the density was significantly correlated in AD mice isolated. The I-to-E synapse density in AD mice exhibited the tendency to inverse correlation with MWM performance. Overall, categorizing hippocampal synapses into 4 classes, we confirmed from a new angle the received view that a higher hippocampal excitability could deteriorate cognition.