Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

Abstract

The central noradrenergic (NA) system is critical for the 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 pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC-NA axons, where released NE acts on b-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, 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-to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC-NA axons coincides with the heightened b-AR function at medial perforant path-dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires b-ARs, and pharmacological blockade of b-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on b-ARs in both behaviors. Thus, a compensatory increase in b-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.

Impairments in fear extinction memory and basolateral amygdala plasticity in the TgF344-AD rat model of Alzheimer’s disease are distinct from non-pathological aging

“…Though unexpected, enhanced extinction in middle-aged TgAD rats is consistent with our previous study of no extinction differences between 10–13-month-old WT and TgAD rats (Goodman et al, 2021) and another reporting 3×Tg-AD mice were better than WT during extinction (Pietropaolo et al, 2008). As detailed above, it is unlikely that diminished salience to the US explains spared extinction, though circuit-level compensation could offer one explanation.…”

“…Consistent with no genotypic difference in fear acquisition in young and middle-aged rats, we recently reported no differences in contextual fear acquisition in a cohort of 10-13-mo-old WT and TgAD rats given a series of uncued foot shocks (Goodman et al, 2021). Aging, however, attenuated acquisition in middle-aged rats, spared acquisition in older-aged WT rats, and impaired acquisition in older-aged TgAD rats, consistent with studies showing aging attenuates, but doesn't grossly impair, acquisition (Villarreal et al, 2004;Kaczorowski et al, 2012).…”

“…Although the hippocampus is critical in contextual fear memory consolidation (Phillips and LeDoux, 1992), there is evidence of hippocampal-independent mechanisms of consolidation (Wiltgen et al, 2006; Kochli et al, 2015). The context deficits in TgAD rats are similar throughout all stages of life, and it is reasonable to suggest the contribution to extinction impairments and contextual generalization is shared between persistent BA hyperactivity and known hippocampal deficits in this rat model (Smith and McMahon, 2018; Goodman et al, 2021). In non-pathological aging, contextual fear memory deficits may also be explained by BA and hippocampal dysfunction given the wide body of literature showing age-related impairments to hippocampal function (Comery et al, 2005; Ohno, 2009; Zeng et al, 2012; Fjell et al, 2014; Zhan et al, 2018; Burke and Foster, 2019).…”

“…Although the hippocampus is critical in contextual fear memory consolidation (Phillips and LeDoux, 1992), there is evidence of hippocampal-independent mechanisms of consolidation (Wiltgen et al, 2006;Kochli et al, 2015). The context deficits in TgAD rats are similar throughout all stages of life, and it is reasonable to suggest the contribution to extinction impairments and contextual generalization is shared between persistent BA hyperactivity and known hippocampal deficits in this rat model (Smith and McMahon, 2018;Goodman et al, 2021).…”

“…Coronal slices (400 µm) containing BLA were prepared using a vibratome (model VT1000P, Leica). As per Goodman et al, 2021, slices were made in low Na + , sucrose-substituted ice-cold artificial CSF (aCSF) containing (in mM): NaCl (85), KCl (2.5), MgSO 4 (4), CaCl 2 (0.5), NaH 2 PO 4 (1.25), NaHCO 3 (25), glucose (25), and sucrose (75), saturated with 95% O 2 , 5% CO 2 , at pH 7.4. Slices were held in a water bath at 26°C for 30 min in standard aCSF containing the following (in mM): NaCl (119.0), KCl (2.5), MgSO4 (1.3), CaCl 2 (2.5), NaH 2 PO 4 (1.0), NaHCO3 (26), and glucose (11), saturated with 95% O 2 , 5% CO 2 , at pH7.4 before transfer to the submersion chamber for recordings.…”