Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

Abstract

The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened β-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.Significance StatementThe locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer’s disease pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.

Dentate Granule Cells Are Hyperexcitable in the Tgf344-Ad Rat Model of Alzheimer’s Disease

“…In addition, we recently reported significant loss of noradrenergic fibers in hippocampus beginning at 6 months (Goodman et al, 2020) when accumulation of hyperphosphorylated tau (pTau) is present in the locus coeruleus (Rorabaugh et al, 2017), the origin of hippocampal noradrenergic (NA) innervation (Loy and Moore, 1979). Furthermore, concurrent with degeneration of hippocampal NA input, we observed heightened function of β adrenergic receptors (β-ARs) at MPP-DGC synapses that were responsible for the enhanced LTP magnitude at 6-months in TgF344-AD rats (Goodman et al, 2020). Importantly, while the β -AR antagonist propranolol prevented the heightened LTP magnitude in TgF344-AD rats, it did not completely abolish the increased in steady state depolarization during the tetanus (Goodman et al, 2020), suggesting that another mechanism is contributing to the increased postsynaptic depolarization.…”

“…Furthermore, concurrent with degeneration of hippocampal NA input, we observed heightened function of β adrenergic receptors (β-ARs) at MPP-DGC synapses that were responsible for the enhanced LTP magnitude at 6-months in TgF344-AD rats (Goodman et al, 2020). Importantly, while the β -AR antagonist propranolol prevented the heightened LTP magnitude in TgF344-AD rats, it did not completely abolish the increased in steady state depolarization during the tetanus (Goodman et al, 2020), suggesting that another mechanism is contributing to the increased postsynaptic depolarization.…”

“…We recently reported increased steadystate postsynaptic depolarization of DGCs during high frequency stimulation and heightened LTP magnitude at MPP-DGC synapses in 6 month old TgF344-AD rats (Smith and McMahon, 2018;Goodman et al, 2020). The increased steady-state depolarization is partially driven by heightened activity of β adrenergic receptors (β-ARs) at MPP-DGC synapses, as a β -AR antagonist does not completely eliminate the increased depolarization (Goodman et al, 2020).…”

“…The copyright holder for this preprint (which this version posted April 14, 2021. ; https://doi.org/10.1101/2021.04.14.439848 doi: bioRxiv preprint (Cohen et al, 2013). In addition, we recently reported significant loss of noradrenergic fibers in hippocampus beginning at 6 months (Goodman et al, 2020) when accumulation of hyperphosphorylated tau (pTau) is present in the locus coeruleus (Rorabaugh et al, 2017), the origin of hippocampal noradrenergic (NA) innervation (Loy and Moore, 1979). Furthermore, concurrent with degeneration of hippocampal NA input, we observed heightened function of β adrenergic receptors (β-ARs) at MPP-DGC synapses that were responsible for the enhanced LTP magnitude at 6-months in TgF344-AD rats (Goodman et al, 2020).…”

“…We previously reported increased postsynaptic depolarization during LTP-inducing stimulation and enhanced LTP magnitude at medial performant path synapses onto dentate gyrus granule cells (MPP-DGC) in 6 month old TgF344-AD rats (Goodman et al, 2020;Smith and McMahon, 2018), a rodent model which more fully recapitulates AD-like pathology in an age-dependent manner (Rorabaugh et al, 2017;Smith and McMahon, 2018;Cohen et al, 2013;Tsai et al, 2014;Pentkowski et al, 2018;Voorhees et al, 2018;Muñoz-Moreno et al, 2018;Bazzigaluppi et al, 2018;Joo et al, 2017;Do Carmo and Cuello, 2013). Specifically, the spatiotemporal spread of synaptic dysfunction in hippocampus begins in the dentate gyrus (DG) prior to area CA1 in both male and female TgF344-AD rats.…”