Recovery of ChAT lmmunoreactivity in Axotomized Rat Cholinergic Septal Neurons Despite Reduced NGF Receptor Expression

Abstract

Previous studies have suggested that target-derived nerve growth factor (NGF) is essential for the survival of cholinergic basal forebrain neurons. Thus, axotomy of septohippocampal neurons in adult rats resulting in the withdrawal of target-derived NGF caused a dramatic loss of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum-diagonal band complex. We have recently shown that this loss of immunolabelled neurons does not indicate cell death, since many septohippocampal cholinergic neurons recover their immunoreactivity for ChAT after a long survival time despite disconnection from target-derived neurotrophins. One possibility would be that these surviving ChAT-immunoreactive neurons have gained access to other, probably local, NGF sources. Here we provide evidence that the recovery of ChAT immunoreactivity after axotomy is not accompanied by a similar recovery of NGF receptor expression in these neurons. In situ hybridization for p75NTR mRNA and trkA mRNA 6 months after bilateral fimbria-fornix transection revealed a substantial loss of labelled cells. In addition, there was a persisting loss of p75NTR-immunoreactive and NGF-immunoreactive medial septal neurons. Cholinergic neurons in controls did not express NGF mRNA, but were heavily immunostained for NGF protein due to receptor-mediated uptake. These data suggest that at least some cholinergic septohippocampal neurons re-express ChAT either independently of NGF or with a reduced need for NGF.

Region-specific activation of microglial cells in the rat septal complex following fimbria-fornix transection

“…In line with this finding, our electron microscopic analysis revealed only very few microglial cells exhibiting signs of phagocytotic activity. These observations are in agreement with our previous studies, which had shown that the majority of septohippocampal projection neurons survive after axotomy but downregulate the synthesis of some cell type-specific markers in the early postlesional period (Peterson et al, 1990;Naumann et al, 1992bNaumann et al, , 1994Naumann et al, , 1997 Kermer et al, 1995;Haas et al, 1996;Hä ge et al, 1996). The presence of activated microglial cells containing myelin debris in the MS after short survival time can be explained, at least in part, by the degeneration of the small direct hippocamposeptal projection to the MS (Tóth and Freund, 1992) and by the degeneration of other hippocampal efferents passing through the septal region (Amaral and Witter, 1995).…”

“…Beside the fact that these axotomized neurons are altered with respect to the expression of neurotrophin receptors (Naumann et al, 1997), we have no evidence for a second wave of neuronal degeneration as observed for motoneurons (Bowe et al, 1988(Bowe et al, , 1992. Even 18 months following ff-t, the longest survival time analyzed so far, the axotomized cholinergic and parvalbumin-containing projection neurons displayed fine structural characteristics of normal MS cells (Kermer et al, 1995;Frotscher et al, 1996).…”

“…An obvious assumption would be that axotomized septohippocampal projection neurons eventually undergo degeneration and cell death in a long-lasting process. However, our previous studies (Naumann et al, 1992b(Naumann et al, , 1994(Naumann et al, , 1997Frotscher et al, 1996) have shown that only very few neurons degenerate and die after axotomy by ff-t. In line with this observation, only 3 weeks postlesion, when some degenerating neurons were observed, a few microglial cells were noticed that by their immunoreactivity for FG indicated phagocytotic activity.…”

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior

“…These converging lines of evidence suggest that following a neurotoxic event, cholinergic neurons, in particular those that have nestin as a cofactor, do not immediately die, but rather enter an atrophic quiescent state in which they do not express the enzymes required to maintain cholinergic transmission. In contrast, a significant portion of cholinergic neurons (30–40%) can be rescued from a pathological state with timely and repeated exposure to NGF (Nagahara et al, 2009; Naumann et al, 1997; Tuszynski and Gage, 1995) or BDNF (Morse et al, 1993). It should be noted that this is the percentage of ChAT+ neurons within the basal forebrain that express nestin.…”

“…The duration of 2-wks for the length of exercise exposure was chosen because this period is sufficient to reverse hippocampal-based cognitive deficits in several other models of cognitive dysfunction (Hall et al, 2014; van Praag et al, 2005). Given that cholinergic remodeling takes time (Gustilo et al, 1999; Naumann et al, 1997), we assessed the recovery of septohippocampal functioning at two time periods: shortly after exercise (24-hrs post exercise) and after an extended adaption period (2-wks post exercise). This design permits the detection of the critical period needed for exercise to modulate the cholinergic septohippocampal system.…”