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

PLoS One. 2019 Jun 24;14(6):e0218036. doi: 10.1371/journal.pone.0218036. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendrites / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / metabolism*
  • Memory Consolidation*
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptor, trkA / agonists*
  • Receptor, trkA / metabolism
  • Spatial Memory

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Receptor, trkA
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding