TrKA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry

Efrain Sanchez-Ortiz, Daishi Yui, Dongli Song, Yun Li, John L. Rubenstein, Louis F. Reichardt, Luis F. Parada

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Dysfunction of basal forebrain cholinergic neurons (BFCNs) is an early pathological hallmark of Alzheimer's disease (AD). Numerous studies have indicated that nerve growth factor (NGF) supports survival and phenotypic differentiation of BFCNs. Consistent with a potential linktoADpathogenesis, TrkA,aNGF receptor,isexpressedincholinergicforebrainneuronal populations including thoseinBF and striatum, and is markedly reduced in individuals with mild cognitive impairment (MCI) without dementia and early-stage AD. To investigate the role of TrkA in the development, connectivity, and function of the BF cholinergic system and its contribution to AD pathology, we have generated a forebrain-specific conditional TrkA knock-out mouse line. Our findings show a key role for TrkA signaling in establishing the BF cholinergic circuitry through the ERK pathway, and demonstrate that the normal developmental increase of choline acetyltransferase expression becomes critically dependent on TrkA signaling before neuronal connections are established. Moreover, the anatomical and physiological deficits caused by lack of TrkA signaling in BFCNs have selective impact on cognitive activity. These data demonstrate that TrkA loss results in cholinergic BF dysfunction and cognitive decline that is reminiscent of MCI and early AD.

Original languageEnglish (US)
Pages (from-to)4065-4079
Number of pages15
JournalJournal of Neuroscience
Volume32
Issue number12
DOIs
StatePublished - Mar 21 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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