Research Article: Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation

Date Published: June 24, 2019

Publisher: Public Library of Science

Author(s): Sylvia Josephy-Hernandez, Iulia Pirvulescu, Mario Maira, Tahar Aboulkassim, Tak Pan Wong, R. Anne McKinney, H. Uri Saragovi, Stephen D Ginsberg.


In the brain, the TrkA receptor for Nerve Growth Factor (NGF) is expressed primarily in the cholinergic system. TrkA/NGF support neuronal health and function, and deficiencies in this axis are associated with progressive cholinergic neuron atrophy and death, and with cognitive deficit in disorders such as Down’s syndrome and Alzheimer’s disease. These observations led to the hypothesis that TrkA agonists may rescue atrophic cholinergic neurons and benefit cognition. Indeed, a small molecule TrkA partial agonist called D3 normalized TrkA signals and improved memory in cognitive impairment models of ageing and an APP mouse model of Alzheimer’s disease. Paradoxically, in young healthy mice chronic delivery of D3 caused impaired memory without impairing learning, a form of anterograde amnesia. Here, we use this as a model to study the mechanisms of impaired memory. In young healthy mice acute or chronic treatment with D3 induces hyperactivation of TrkA-mediated signals in hippocampus, and causes a deficit in hippocampal-dependent memory consolidation proximal to drug exposure, without affecting learning or memory retrieval. The impairment after acute drug exposure is reversible. The impairment after long-term drug exposure is irreversible, likely due to a decrease in hippocampal CA1 neuron basal arborization. These findings support the notion of a homeostatic role for TrkA in memory, and demonstrate the differential outcomes of TrkA (hyper)activation in healthy versus disease states.

Partial Text

Alzheimer’s disease (AD) is the most common type of dementia, but the etiology and pathophysiology remain elusive, and this contributes to the lack of effective treatments [1]. Cholinergic neurons are key to learning and memory, and their atrophy underlies the memory-impairment phenotype of AD and ageing [2]. However, the cholinergic mechanisms that contribute to data processing (learning), data consolidation (storage), data retrieval (recall), and reconsolidation after recall are still poorly understood at a molecular level [3].

Previously, we showed that a chronic 2-week delivery of D3 provided memory benefits in cognitively impaired mice and rats. However, in young healthy mice a chronic 2-week delivery of D3 caused memory impairment without causing a learning deficit. This unexpected effect lasted for months after drug wash-off [4, 22], suggesting long-lasting transcriptional or anatomical changes caused by drug treatment in young healthy mice. Here, we explore the mechanisms of memory impairment and compare the biochemical, anatomical, and behavioral effects of acute and chronic D3-treatment paradigms.

The data show that D3-intraventricular delivery leads to hyper-activation of TrkA signals both in the acute and the chronic treatment paradigms, and a behavioral phenotype reminiscent of anterograde amnesia. Acute or chronic D3-treatment of young healthy mice conveys memory impairment due to failure in memory consolidation, in a time period proximal to drug action, which in the acute paradigm is reversible but in the chronic paradigm is sustained long after drug-wash-off. In the acute treatment paradigm the memory deficits are reversible, and there are no detectable anatomical changes in hippocampus. In the chronic treatment paradigm the memory deficits are sustained, this is correlated with and likely due to a decrease in hippocampus CA1 neuronal branching. Table 1 summarizes a comparison of the data obtained after acute and chronic delivery of the pharmacological TrkA agonist D3.

Reportedly, loss of TrkA density/activity correlates with cholinergic neuronal atrophy and death, and with disease progression in in rodent models of memory impairment [12] and humans [14, 15, 31]. These observations led to the hypothesis that selective activation of TrkA may be neuroprotective and beneficial to memory [17], a concept that has been proven experimentally in animal models of disease [4, 22].




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