Lesion-induced sprouting of commissural/associational axons and induction of GAP-43 mRNA in hilar and CA3 pyramidal neurons in the hippocampus are diminished in aged rats

Abstract

Removal of synaptic connections following a partial deafferentation lesion results in a sprouting of remaining afferents that terminate near the denervated area. However, while the ability to form new synapses in response to injury has been reported in both young and aged rats, previous studies have suggested that the injury-induced response in the hippocampus of aged rats may be delayed and/or not as extensive as compared to young adults. Given that growth associated proteins are central for the regulation of neurite outgrowth during both development and regeneration, we were interested in determining if the magnitude and time course of the sprouting response of hippocampal neurons to deafferentation might correlate with induction of growth associated proteins and whether these parameters could be modulated with age. For our studies we used the Holmes fiber stain to determine the expansion of the C/A fiber plexus following denervation and compared the time course of the sprouting response with that observed by in situ hybridization for the neurite outgrowth proteins, growth associated protein-43 (GAP-43), superior cervical ganglion-10 (SCG-10), and neurofilament-68 (NF-68) at various time points after the lesion for each age group. We found that the commissural/associational (C/A) fiber plexus expanded by 45% in young adult rats at 30 and 45 d postlesion and was accompanied by a significant increase in expression of GAP-43 mRNA in both ipsilateral and contralateral hilar and CA3 pyramidal neurons, the cell bodies of origin for the C/A pathway. In contrast, a dampened sprouting response was observed in aged rats at all time points postlesion and coincided with a lack of induction of any of the growth-associated proteins. These results suggest that GAP-43 is involved in outgrowth of C/A axons in the hippocampus in response to a partial deafferentation lesion. However, factors that stimulate neurite outgrowth and upregulate GAP-43 mRNA in response to a partial deafferentation lesion diminish with age.

Estrogen and Aging Affect the Subcellular Distribution of Estrogen Receptor-α in the Hippocampus of Female Rats

“…This phenomenon of an impaired response to ER-␣ is consistent with a study demonstrating that ER-␣ levels in the hypothalamus are decreased by estrogen in young but not aged rats (Funabashi et al, 2000). The decreased number of synapses that contain ER-␣-IR in aged animals as well as the decreased regulation of ER-␣-IR by estrogen in these same animals suggest that age-related shifts in ER-␣ may render the aged brain less plastic, which is consistent with other studies supporting a decrease in synaptic plasticity in the aging hippocampus (Cotman and Scheff, 1979;Scheff et al, 1980;Hoff et al, 1982a,b;West, 1984;Schauwecker et al, 1995;Stone et al, 2000). In the present study, only one postovariectomy interval and estrogen-replacement regimen was examined.…”

Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis

“…These include minimal increase in DG neurogenesis observed after stroke in aged animals (Jin et al, 2004;Darsalia et al, 2005), and an unchanged neurogenesis seen after an intracerebroventricular KA-induced hippocampal injury in middle-aged and aged animals . Lack of significant increase in DG neurogenesis after seizures, stroke or hippocampal injury during old age is also consistent with diminished overall injury-induced plasticity in the hippocampus with age (Schauwecker et al, 1995;Woods et al, 1998;Shetty and Turner, 1999;Maughan et al, 2000;Abdel-Rahman et al, 2004;Shetty et al, 2004).…”

“…This is an important issue because the incidence of SE is much higher during old age (Towne, 2007). Moreover, characterization of the postlesion plasticity indicate that aging diminishes the synaptic reorganization and upregulation of neurotrophic factors following injury in the hippocampus (Schauwecker et al, 1995;Woods et al, 1998;Shetty and Turner, 1999;Shetty et al, 2004). Furthermore, studies suggest that increased neurogenesis and enhanced ectopic migration of newly born granule cells into the dentate hilus after acute seizures or SE likely contributes to or exacerbates the development of chronic epilepsy after SE (Scharfman et al, 2000(Scharfman et al, , 2002(Scharfman et al, , 2003Jung et al, 2004;Pierce et al, 2005;McCloskey et al, 2006;Parent, 2007;Scharfman and Gray, 2007).…”

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

“…Other reflections of hippocampal plasticity may be attenuated with age as well. Previous studies have described a decreased sprouting response and synaptogenesis in the hippocampus, as well as a reduced up-regulation of growth-associated proteins in the hilus of aged animals after a perforant path lesion (56)(57)(58)(59)(60)(61)(62), and we observed an attenuated up-regulation of NR1 in the dentate gyrus of aged animals after a perforant path lesion (M.M.A, A. H. Gazzaley, and J.H.M., unpublished observations). Although these data suggest that some elements of synaptic plasticity are blunted in aged animals, they do not address plasticity at the level of NMDA receptor subunit representation at the synapse.…”