Introduction:
Hippocampal hyper-excitability is a causative factor in memory impairment and has been documented in many animal models for Alzheimer’s disease (AD). Here, we sought to track AD-related prodromal changes in hippocampal synaptic strength and plasticity in the TgF344-AD rat model, which exhibits age-dependent beta-amyloid (Aß) aggregation, tauopathy and neuroinflammation.
Methods:
Electrophysiology: Evoked responses in dorsal CA1 were recorded following CA3 Schaffer stimulation in urethane-anaesthetised 6- and 9-month-old male TgF344-AD (TG) and wild-type (WT) rats, to determine the induction properties for short- and long-term synaptic plasticity and baseline connectivity.
Post-mortem: Parvalbumin (PV) levels were measured in dorsal hippocampus by Simple Western analysis and immunohistochemistry of age-matched rats.
Results:
In contrast to 6-month-old TG rats, the 9-month-old TGs showed significantly smaller paired-pulse facilitation, and this cohort of TG animals also displayed an upwardly-shifted baseline input/output curve. Long-term potentiation induced by high-frequency stimulation was significantly reduced in CA1 of 6- and 9-month-old TG rats. LTP depotentiation tested in 6-month-old rats was much stronger in TG compared to WT. Immunohistochemical analysis revealed significantly lower PV levels in CA2/3 region, but not CA1 or dentate gyrus of the hippocampus in 9-month-old TG rats. Work is underway to determine PV changes at 6 months old.
Conclusions:
These results suggest that reduced inhibition upstream of the CA3-CA1 synapse leads to abnormal changes in synaptic plasticity, which might imply a possible mechanism for disease progression at pre-symptomatic stage of AD.
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