Early‐stage hippocampal hyperexcitability and impaired synaptic plasticity in the TgF344‐AD rat model of Alzheimer’s disease

Background The transgenic TgF344‐AD (TG) rat is emerging as a useful model for investigating age‐dependent AD features that include behavioural, electrophysiological and pathological phenotypes of relevance to disease. In this study we investigated changes related to early stages of AD in 9 month old animals. Method Male and female TG rats and wild‐type (WT) littermates undertook longitudinal behavioural testing at 3, 6 & 9 months (n=6‐13/sex‐genotype combination) and were tested for: (i) hippocampus‐dependent rapid place learning in a delayed‐matching‐to place watermaze (DMP) test, (ii) novel object recognition (NOR) memory, (iii) expression of startle/pre‐pulse inhibition; and (iv) open‐field locomotor activity. In another cohort of rats at 9 months (n=8 males per genotype), spontaneous and evoked activities were record and measured in hippocampal CA3–>CA1 circuit to study synaptic plasticity using in vivo electrophysiology under urethane anaesthesia. Following behavioural or electrophysiology testing brains were collected for post‐mortem analyses (n=10 males per genotype). GABAergic and synaptic markers including parvalbumin, GAD67, GABAA α5, SNAP‐25 and PSD95 were measured by Simple Western analysis in the frontal cortex, prefrontal cortex, dorsal and ventral hippocampus. Result Behaviour: WT rats showed poor DMP performance with no clear genotype effect. Object exploration was low with no significant NOR. We found startle and locomotor sex differences, replicating previous reports. Interestingly, at 9 months, TG rats showed locomotor hypoactivity at the beginning and hyperactivity at the end of the 30‐min open‐field test, indicating impaired habituation, which may reflect impaired hippocampal contextual memory. Electrophysiology: 9‐month‐old TG rats showed reduced long‐term potentiation with an increased baseline connectivity. A general decrease in power across frequency bands was found in the TG, especially for theta band. Western analysis: TG rats showed reduced levels of parvalbumin with a clear effect of genotype at 9‐months. There was no detectable changes in synaptic markers. Conclusion Impaired locomotor habituation of TG rats suggests abnormal hippocampal function emerges around 9 months, reflected by impaired hippocampal CA1 plasticity. A reduction of parvalbumin was also seen in the TG animals at this age. However, poor memory performance may limit the suitability of the TG model for testing clinically relevant memory deficits.