Loss of NGF-TrkA Signaling from the CNS Is Not Sufficient to Induce Cognitive Impairments in Young Adult or Intermediate-Aged Mice

Abstract

Many molecules expressed in the CNS contribute to cognitive functions either by modulating neuronal activity or by mediating neuronal trophic support and/or connectivity. An ongoing discussion is whether signaling of nerve growth factor (NGF) through its high-affinity receptor TrkA contributes to attention behavior and/or learning and memory, based on its expression in relevant regions of the CNS such as the hippocampus, cerebral cortex, amygdala and basal forebrain. Previous animal models carrying either a null allele or transgenic manipulation of Ngf or Trka have proved difficult in addressing this question. To overcome this problem, we conditionally deleted Ngf or Trka from the CNS. Our findings confirm that NGF-TrkA signaling supports survival of only a small proportion of cholinergic neurons during development; however, this signaling is not required for trophic support or connectivity of the remaining basal forebrain cholinergic neurons. Moreover, comprehensive behavioral analysis of young adult and intermediate-aged mice lacking NGF-TrkA signaling demonstrates that this signaling is dispensable for both attention behavior and various aspects of learning and memory.

Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study

“…Moreover, suppression of trkA signaling per se in young may not impose any inimical effects on the BF cholinergic system. This view is supported by a previous study showing that forebrain-specific targeted deletion of NGF or trkA receptors exerted detrimental effects on BF cholinergic neurons during postnatal development but did not impact learning and memory performance when assessed in either young adult or intermediate-aged mice (Müller et al, 2012). …”

NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

“…Therefore, we hypothesized that genetic deletion of NGF in these cells should yield a bone phenotype analogous to that seen in TrkA F592A ;Thy1-YFP mice. To explore this idea, mice with floxed NGF alleles (NGF fl/fl ) (Muller et al, 2012) were mated to mice carrying Col2-CreER T , a construct which has been used extensively to map the fate of early perichondrial precursors (Ono et al, 2014). Tamoxifen (1 mg) and progesterone (1 mg) were administered to timed pregnant mice at embryonic day 11.5, a time point at which recombination occurs throughout the developing limb, including the proliferating cartilage and perichondrium (Nakamura et al, 2006).…”

“…NGF-eGFP mice, which express eGFP under the control of the mouse NGF promoter, were generously donated by the Kawaja lab (Kawaja et al, 2011). Mice with floxed NGF alleles were generated in the Minichiello lab (Muller et al, 2012). Col2-CreER T mice, which can be induced by tamoxifen to express Cre recombinase in cells that express Type II collagen (Nakamura et al, 2006), are available commercially (Jackson Laboratory, Stock #006774).…”

Growth factor signaling and memory formation: temporal and spatial integration of a molecular network

“…Interestingly, cholinergic cells are highly susceptible to Alzheimer's disease (AD) pathology (Auld et al 2002;Mesulam 2004), and NGF has been used as a successful therapy in aged rodents and an AD model (Fischer et al 1987(Fischer et al , 1991Backman et al 1996;Frick et al 1997;Capsoni et al 2012). NGF effects in young adult rodents is conflicting (Van der Zee et al 1995;Backman et al 1996;Muller et al 2012), indicating that the therapeutic effects of NGF may only be exerted in impaired states (Fischer et al 1991;Janis et al 1995;Backman et al 1996) and may actually impair memory in the absence of pathology (Backman et al 1996).…”