Deficits in synaptic function occur at medial perforant path-granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer’s Disease Rat Model

Alzheimer’s disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density at two hippocampal synapses in male and ovariectomized female TgF344-AD rats and wildtype littermates, prior to reported behavioral deficits. Decreased basal synaptic transmission begins at medial perforant path-dentate granule cell (MPP-DGC) synapses prior to Schaffer-collateral-CA1 (CA3-CA1) synapses, in the absence of a change in paired-pulse ratio (PPR) or dendritic spine density. N-methyl-D-aspartate receptor (NMDAR)-dependent LTP magnitude is unaffected at CA3-CA1 synapses at 6, 9, and 12 months of age, but is significantly increased at MPP-DGC synapses in TgF344-AD rats at 6 months only. Sex differences were only observed at CA3-CA1 synapses where the decrease in basal transmission occurs at a younger age in males versus females. These are the first studies to define presymptomatic alterations in hippocampal synaptic transmission in the TgF344-AD rat model. The time course of altered synaptic transmission mimics the spread of pathology through hippocampus in human AD and provides support for this model as a valuable preclinical tool in elucidating pathological mechanisms of early synapse dysfunction in AD. synaptic efficacy precede reported hippocampus dependent learning and memory deficits in the novel comprehensive TgF344-AD rat model. Together our data show that at ages when soluble A β , hyper-p-tau, and gliosis are increased, but prior to reported hippocamapal-dependent behavioral deficits 2013), basal synaptic strength is weakened and LTP is pathologically altered. Specifically, the maximum strength of basal excitatory transmission is decreased as early as 6 months of age at MPP-DGC synapses in TgF344-AD rats compared to WT littermate controls. This decreased basal synaptic connectivity at MPP-DGC synapses occurs prior to weakened maximum synaptic transmission at CA3-CA1 synapses, which begins at 9 months in males and 12 months in females, demonstrating a sex bias at CA3-CA1 synapses. Importantly, the decreased strength of basal transmission occurs in the absence of a change in the PPR or dendritic spine density at either synapse. The magnitude of NMDAR-dependent LTP is pathologically enhanced only at 6 months at MPP-DGC synapses in both sexes, while at CA3-CA1 synapses, the LTP magnitude is unchanged. Overall, these results show that hippocampal synaptic dysfunction occurs earlier at synapses emanating from EC during the presymptomatic phase of the disease, recapitulating what is known to occur in human hippocampus in subjects with AD Furthermore, the finding that synaptic dysfunction occurs prior to reported learning and memory deficits corroborates results from human fMRI studies during preclinical AD that in basal transmission, unaltered presynaptic release probability, normal CA3-CA1 LTP and pathologically enhanced MPP-DGC LTP magnitude predict a loss of postsynaptic AMPARs, altered passive membrane properties, and/or altered excitation/ inhibition balance.