Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats

Abstract

Positive allosteric modulators of AMPA-type glutamate receptors (ampakines) have been shown to rescue synaptic plasticity and reduce neuropathology in rodent models of cognitive disorders. Here we tested whether chronic ampakine treatment offsets age-related dendritic retraction in middle-aged (MA) rats. Starting at 10 months of age, rats were housed in an enriched environment and given daily treatment with a short half-life ampakine or vehicle for 3 months. Dendritic branching and spine measures were collected from 3D reconstructions of Lucifer yellow-filled CA1 pyramidal cells. There was a substantial loss of secondary branches, relative to enriched 2.5-month-old rats, in apical and basal dendritic fields of vehicle-treated, but not ampakine-treated, 13-month-old rats. Baseline synaptic responses in CA1 were only subtly different between the two MA groups, but long-term potentiation was greater in ampakine-treated rats. Unsupervised learning of a complex environment was used to assess treatment effects on behavior. Vehicle-and drug-treated rats behaved similarly during a first 30 min session in the novel environment but differed markedly on subsequent measures of long-term memory. Markov sequence analysis uncovered a clear increase in the predictability of serial movements between behavioral sessions 2 and 3 in the ampakine, but not vehicle, group. These results show that a surprising degree of dendritic retraction occurs by middle age and that this can be mostly offset by pharmacological treatments without evidence for unwanted side effects. The functional consequences of rescue were prominent with regard to memory but also extended to self-organization of behavior.

Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol

“…Thus, drug combinations activating these pathways may constitute candidates for enhancing human synaptic plasticity, learning, and memory. Ampakines are another class of drugs that may be effective for augmentation of learning (Lauterborn et al 2016). It would be of interest to examine the efficacy of treatments that combine an ampakine with an activator of ERK, PKA, or both.…”

Early life diet containing prebiotics and bioactive whey protein fractions increased dendritic spine density of rat hippocampal neurons

“…Losses of large‐diameter and mushroom‐type spines, in contrast, are more closely related to impairments of long‐term memory storage and neurodegeneration, especially in hippocampus (Hara et al, 2012), as observed in Alzheimer's Disease rodent models (Penazzi et al, 2016). Evidence for the inverse exists as well: elevations of both long‐thin and mushroom spines correlate with multiple forms of cognitive enhancement (Kitahara et al, 2016; Lauterborn et al, 2016). This effect was observed within the MML of the dentate gyrus, which along with the outer molecular layer, receives perforant pathway inputs from the entorhinal cortex.…”

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

“…Recent work has begun to address the question of whether long-term ampakine treatment could be beneficial by assessing if this treatment regimen offsets the deleterious effects of brain aging in hippocampus (Lauterborn et al, 2016). In these studies, 10-month old middle-aged rats were treated with the ampakine CX929 (5 mg/kg in 10% honey in water) or vehicle orally on a 5 day-on / 2 day-off schedule for three months and housed in an enriched environment during this period.…”