Research reportProdynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance
Introduction
The endogenous opioid peptide dynorphin, expressed widely in the central nervous system [17], [22], [46], [47] and particularly prominent in mossy fiber terminals of the hippocampal formation [26], [50], has been implicated in modulating learning and memory. Dynorphin peptides are pharmacological agonists at κ-opioid receptors [1], and to a lesser extent δ and μ receptors [13], but have been observed to interact with other non-opioid targets like the NMDA receptor [2], [3], [4], [40] and even the excitatory amino acids themselves [49]. The effects of dynorphins in learning and memory are supported by reports of the ability of endogenous dynorphin to inhibit neural plasticity by blocking long-term potentiation (LTP) at mossy fiber-CA3 pyramidal cell synapses, perforant path-granule cell synapses, and mossy fiber recurrent synapses in the dentate gyrus [42], [43], [45]. The mechanisms involved include presynaptic inhibition of glutamate release via κ-opioid receptors and postsynaptic modulation of LTP as a retrograde inhibitory neurotransmitter [44], [45], [48].
Behavioral studies have documented an inhibitory effect of this neuropeptide on learning and memory. In vivo approaches in rats have demonstrated impairment of spatial memory upon intrahippocampal injection of dynorphin A(1-8) [25] or dynorphin B [38]. Dynorphin was also found to dose-dependently impair retention in an inhibitory avoidance task in mice [18]. The findings that dynorphin is elevated in hippocampus and frontal cortex of aged rats, especially memory-impaired rats [12], [20], further suggested a possible involvement of dynorphins in age-related memory deficits. Of particular relevance to human disease, dynorphin A is markedly elevated in the frontal cortex of patients with Down syndrome or Alzheimer's disease (AD) [37] and in mice overexpressing human amyloid precursor protein [8]. Large increases in κ-opioid receptor levels have also been noted in brains of AD patients [16], and cognitive performance in AD patients can be improved by the nonselective opioid antagonist naloxone [36].
A definitive causative role of increases in dynorphin in producing memory deficits associated with normal aging has not been clearly established, and cellular genetic mechanisms related to its effect in the hippocampus and other parts of the brain have not been carefully explored. To investigate the mechanisms underlying age-dependent changes in spatial learning and memory and the potential role of dynorphin in mediating these changes, we examine in this study the effects of aging in knockout mice lacking the coding exons for the precursor prodynorphin (Pdyn) [39].
Section snippets
Animal subjects
All animals in this study were wild-type (WT) or Pdyn−/− mice that were maintained in an approved animal facility at the University of Kentucky. WT mice were derived from the 129SvEv-Tac line, and Pdyn−/− mice were originally obtained by targeted deletion of the coding exons of the prodynorphin gene and bred into a 129SvEv-Tac background as described [39]. The aged mice included in this analysis ranged from 13 to 17 months at the time of testing, averaging 15.8 ± 2.0 (mean ± S.D.) months for WT and
Water maze
A total of 18 aged Pdyn−/− mice, 17 aged WT mice, 11 young Pdyn−/− mice, and 13 young WT mice were initially tested on the cue discrimination task to assess visual acuity, sensorimotor function, and general motivation. Two animals, both aged Pdyn−/− mice, failed to consistently locate the visible platform and were removed from the study. Based on the remaining mice, all four groups showed significant learning effects across the four blocks of the cued task (Fig. 1), as determined by a
Discussion
The present study confirms a significant impairment with aging in the spatial water maze task [11], [24], [34]. The age-related impairment is clearly observable for the 13- to 17-month mice used in this study as demonstrated by the significant differences shown in the vast majority of the quantitative indicators of learning and memory. Although aging confers an approximately 15–20% decrease in swim speed in our study, motor activity by itself is unlikely to account for most of the
Acknowledgements
This work has been supported by NS 044157 and DAMD17-9919497 to G.B.; AG14979 and an Evelyn F. McKnight Brain Research Grant to T.C.F.; MH65055-01 and a Howard Hughes Medical Institute predoctoral fellowship to X.V.N.
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2018, Progress in Brain ResearchCitation Excerpt :The effects of aging on KOR/DYN signaling in rats are conserved across species, with many similar reports in mice. Poor performance on the Morris water maze was correlated with elevated DYN levels in the frontal cortex (Menard et al., 2013; Nguyen et al., 2005) and hippocampus (Menard et al., 2013) of aged wild-type mice. Conversely, aged Pdyn knockout (KO) mice exhibited enhanced learning and memory relative to aged wild-type mice on the Morris water maze (Menard et al., 2013, Nguyen et al., 2005).
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2014, NeuropharmacologyCitation Excerpt :Similarly to our result previous studies generally found an amnesic effects of dynorphins (Magnusson et al., 2009) or synthetic KOR agonists (Castellano et al., 1988; Sandin et al., 1998; Schindler et al., 1987). Based on these findings it was assumed that the increase in Pdyn expression in ageing contributes to the development of age-related cognitive deficits (Jiang et al., 1989; Nguyen et al., 2005) by decreasing glutamate signalling (Zhang et al., 1991). The possible relation between dynorphin signalling and cognitive abilities was supported by a human genetic study (Kolsch et al., 2009).
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2011, Trends in Pharmacological SciencesCitation Excerpt :In a related microarray study, young adult rats were treated with the muscarinic acetylcholine antagonist scopolamine to induce a type of amnesia similar to the cognitive impairment seen in AI animals [56]. Intriguingly, dynorphin was overexpressed in the scopolamine-treated animals compared with controls [55]. This neuropeptide might play a role in the control of hippocampal glutamatergic input.