G Model

ARTICLE IN PRESS

NSL 31146 1–6

Neuroscience Letters xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet

Research article

1

2

3

Q1

4

Q2

5 6 7 8

Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats Yuan-Jian Yang a,b , Hai-Bo Chen b , Bo Wei b , Wei Wang c , Ping-Liang Zhou b , Jin-Qiong Zhan a , Mao-Rong Hu b , Kun Yan a , Bin Hu b,∗ , Bin Yu a,∗∗ a

Department of Medical Experimental Center, Jiangxi Mental Hospital, Nanchang 330029, PR China Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, PR China c Department of Neurology, The Second Affiliated Hospital, Nanchang University, Nanchang 330025, PR China b

9

10 11 12 13 14

h i g h l i g h t s • Aged rats were separated into aged-umimpaired and aged-impaired rats. • Surface GluR1 expression in hippocampal CA1 is reduced in aged-impaired rats. • Lower surface GluR1 level is associated with worse behavioral performance.

15

16 30

a r t i c l e

i n f o

a b s t r a c t

17 18 19 20 21 22

Article history: Received 8 December 2014 Received in revised form 27 January 2015 Accepted 13 February 2015 Available online xxx

23 24 25 26 27 28 29

31 32

Keywords: Aging Cognitive decline AMPA receptor GluR1 Hippocampus

Individual differences in cognitive aging exist in humans and in rodent populations, yet the underlying mechanisms remain largely unclear. Activity-dependent delivery of GluR1-containing AMPA receptor (AMPARs) plays an essential role in hippocampal synaptic plasticity, learning and memory. We hypothesize that alterations of surface GluR1 expression in the hippocampus might correlate with age-related cognitive decline. To test this hypothesis, the present study evaluated the cognitive function of young adult and aged rats using Morris water maze. After the behavioral test, the surface expression of GluR1 protein in hippocampal CA1 region of rats was determined using Western blotting. The results showed that the surface expression of GluR1 in the hippocampus of aged rats that are cognitively impaired was much lower than that of young adults and aged rats with preserved cognitive abilities. The phosphorylation levels of GluR1 at Ser845 and Ser831 sites, which promote the synaptic delivery of GluR1, were also selectively decreased in the hippocampus of aged-impaired rats. Correlation analysis reveals that greater decrease in surface GluR1 expression was associated with worse behavioral performance. These results suggest that reduced surface GluR1 expression may contribute to cognitive decline that occurs in normal aging, and different pattern of surface GluR1 expression might be responsible for the individual differences in cognitive aging. © 2015 Published by Elsevier Ireland Ltd.

Aging can have a pronounced impact on cognitive function across rodents, nonhuman primates, and humans. Although cognitive

Abbreviations: MWM, Morris water maze; AU, age-unimpaired; AI, ageimpaired; AMPARs, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; NMDARs, N-methyl-d-aspartic acid receptors; LTP, long-term potentiation. ∗ Corresponding author at: Department of Psychiatry, Jiangxi Mental Hospital, 43# Shangfang Road, Nanchang 330029, PR China. Tel: +86 791 88330161. ∗∗ Corresponding author at: Department of Medical Experimental Center, Jiangxi Mental Hospital, 43# Shangfang Road, Nanchang 330029, PR China. Tel.: +86 791 88121297. E-mail addresses: jxmh [email protected] (B. Hu), jxmh [email protected] (B. Yu).

decline is widespread enough to be often considered a common aspect of aging, some older individuals maintain high cognitive functioning [10,19]. However, the molecular mechanisms for such differences in cognitive abilities of older individuals remain elusive. It is widely accepted that encoding new memories involves activity-dependent modifications of the strength or efficacy of synaptic transmission in neural circuits through mechanisms of synaptic plasticity like long-term potentiation (LTP) and long-term depression (LTD) [13]. Research on animals has documented that alterations in the induction of LTP in hippocampal circuits are likely the neural basis for memory decline associated with aging [3,5,21]. Indeed, plenty of studies have showed correlations between alterations in synaptic plasticity and severity of cognitive impairments

http://dx.doi.org/10.1016/j.neulet.2015.02.030 0304-3940/© 2015 Published by Elsevier Ireland Ltd.

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

33 34 35 36 37 38 39 40 41 42 43 44 45

G Model NSL 31146 1–6 2

ARTICLE IN PRESS Y.-J. Yang et al. / Neuroscience Letters xxx (2015) xxx–xxx

Fig. 1. Behavioral characterization on a task that recruits hippocampus structures identifies a subpopulation of aged rats that are impaired relative to young adults. (A) The escape latency to reach the hidden platform. The aged-impaired rats (AI) performed significantly worse than the aged-unimpaired rats (AU) and young controls during the last five trial days (days 2–6). (B) The time spent in the target quadrant in probe trial. Young and AU rats showed comparable task retention, while AI rats showed retention deficit on the test. (C) Platform crossings in probe trial. Both young and AU rats displayed more platform crossings compared to the AI rats. (D) The visible platform task. There were no significant differences between any groups for the latency to find the visible platform. (E) The swimming speed. There was no significant difference in swimming speed among each animal group. The number of rats in young, AU and AI groups were 11, 10 and 10, respectively. Bars represent the mean ± S.E.M. **P < 0.01 compared to young group.

46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76

in older rodents [3,12,17]. Thus, the dysfunction of proteins that are closed to synaptic plasticity might be correlated with aging-related cognitive decline. AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) are the main transducers of fast excitatory neurotransmission in the mammalian brain, and are targets for multiple signaling pathways that regulate the strength of glutamatergic excitatory synapses. AMPARs are tetramers comprised of four glutamate receptor subunits, GluR1–GluR4. Accumulated evidence has demonstrated that synaptic insertion of GluR1containing AMPARs contributes to the synaptic potentiation during LTP, experience-dependent neuronal plasticity as well as learning and memory [6,15]. Accordingly, mouse lacking the gene encoding the GluR1 subunit exhibits impaired hippocampal LTP and spatial memory [16]. Blocking the synaptic delivery of endogenous GluR1-containing AMPARs by a fragment of the GluR1-cytoplasmic tail prevents the induction of LTP in the CA1 region and impaired contextual memory [15]. The role of GluR1-containing AMPARs in aging-associated cognitive deficits has been investigated by examining the total levels of GluR1 protein in the hippocampus of aged animals, while the findings were contradictory. Some studies reported that there was no significant difference in GluR1 expression in the hippocampus between young adult and aged rodents [10,23], while others showed age-related decrease or increase [1,2,14]. The functional properties of AMPARs depend on its density in the plasma membrane. So far, no study has addressed the surface expression of GluR1 in the hippocampus of aged rats. It is therefore great interest to explore whether aging process would induce changes in the surface expression of GluR1 subunit in the hippocampus, and if so, whether this alteration is related to the cognitive decline of aged individual.

In present study, we used a well-characterized model in which aged rats are classified based on the presence or absence of memory deficits, with associated functional alterations in the hippocampus [7]. The cognitive function of rat was evaluated using Morris water maze (MWM) and the protein level of surface GluR1 in hippocampal CA1 region was determined using Western blotting. Male Sprague–Dawley (SD) rats were purchased from the Beijing HFK Bioscience Company (Beijing, China) and were housed in groups (three to four rats per cage). The animals were maintained on a controlled light-dark cycle at a constant temperature (22 ± 2 ◦ C) with ad libitum access to food and water. They were 6 (young adult) or 24 (aged) months of age at the time of the study and any animals with gross defects (such as tumors and overt blindness) were excluded. The research was conducted in accordance with the EC Directive 86/609/EEC and with the Guide for Care and Use of Laboratory Animals as adopted and promulgated by the United National Institutes of Health. All experimental protocols were approved by the Review Committee for the Use of Human or Animal Subjects of Jiangxi Mental Hospital. The Morris water maze task was processed according to our previous protocols with some modifications [20]. A circular pool (diameter 120 cm, height 60 cm) was filled with water (22 ◦ C) to a depth of 40 cm, covering the surface with floating black resin beads. The pool was located in a dimly lit, soundproof test room with various visual cues, including a white-black colored poster on the wall, a halogen lamp, a camera and the experimenter. The maze was divided into four quadrants and a black escape platform was located in one quadrant 1.5 cm below the water surface. The position of the platform and cues remained the same throughout the entire experiment. The rat was placed in the water at the perimeter of the pool and given 120 s to find the platform, and was allowed to

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107

G Model NSL 31146 1–6

ARTICLE IN PRESS Y.-J. Yang et al. / Neuroscience Letters xxx (2015) xxx–xxx

3

Fig. 2. The protein levels of total, cell surface and phosphorylated GluR1 in the hippocampal CA1 region of rats. (A and B) Representative western blots of total GluR1 expression and histogram showing the total GluR1 levels in tissues from hippocampal CA1 region of three groups. (C and D) Representative western blots of surface and intracellular GluR1 expression and histogram showing the surface GluR1 levels in tissues from hippocampal CA1 region of three groups. (E–G) Representative western blots of phosphorylated GluR1(Ser831) and GluR1(Ser845) and histogram showing the phosphorylated GluR1 levels in tissues from hippocampal CA1 region of three groups. The number of rats in young, AU and AI groups were 11, 10 and 10, respectively. Bars represent the mean ± S.E.M. **P < 0.01 compared to young rats.

Fig. 3. Correlations between behavior performance in the Morris water maze task and the surface GluR1 level in hippocampal CA1 region in the aged rats. There was a significantly negative correlation between the surface GluR1 level and the escape latency in the sixth training day (A) and a positive correlation between the surface GluR1 level and the time spent in target quadrant in the probe trial (B).

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

G Model NSL 31146 1–6 4 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173

ARTICLE IN PRESS Y.-J. Yang et al. / Neuroscience Letters xxx (2015) xxx–xxx

rest on it for 20 s. The animals failed to find the location within the given time were gently guided to the platform and were allowed to stay on it for 20 s. Each rat was given three trials daily for six consecutive days, with an intertrial interval of 60 s. During these trials, rats were randomly placed in the pool at different quadrant positions except for the platform quadrant. In each trial, the escape latency to locate the platform, the swimming distance and mean swimming speed were recorded. To assess the spatial memory retention, a spatial probe trial was performed 24 h after last training by removing the platform from the water tank. In this test, rats were allowed to swim freely for 60 s and the time spent in the target quadrant was recorded. After the probe trial, rats were subjected to a visible platform task, in which the escape platform was raised above the water and the time taken to reach the platform was assessed. All movement in the whole trials was recorded and analyzed by a computerized video imaging analysis system (ANY-maze; Wood Dale, IL). The mean data from daily test were used for statistical analysis. The cognitive status of an aged rat was determined on the basis of its escape latencies on days 3–6 of testing in the MWM relative to the mean latency of young controls. An aged-impaired (AI) rat was defined as one whose mean latency (across days 3–6 of testing) differed by >2.0 standard deviations (SDs) from that of young controls. An aged animal was considered aged-unimpaired (AU) if its mean latency score was 0.05). One day after the training, the spatial memory ability was evaluated by a probe test, in which the time spent in the target quadrant of the pool was recorded when the hidden platform was removed. It was shown that aged-unimpaired rats spent comparable time in the target quadrant relative to that of the young rats, whereas the aged-impaired rats showed no preference for the target quadrant (Fig. 1B; main effect of group-ANOVA, F(2, 28) = 24.117, P < 0.01). Furthermore, the aged-impaired rats showed fewer platform crossings than the young group, while the aged-unimpaired and young rats did not significantly differ from each other (Fig. 1C; main effect of group-ANOVA, F(2, 28) = 11.258, P < 0.01). In the visible platform test, we did not observe significant difference between aged and young rats in escape latency or swimming speed (Fig. 1D and E, P > 0.05), indicating normal vision and locomotor activity. These results indicate that aged rats in this study population exhibited individual differences in cognitive ability as assessed using the indexes of escape latency during training session and time spent in target quadrant during probe trial. Fig. 2 shows the total and surface GluR1 expressions and the phosphorylations of GluR1 at Ser845 and Ser831 sites in the hippocampal CA1 region of rats. Consistent with previous report [23], we showed that aging process had no significant influence on the total GluR1 expression in the hippocampus of rats, as the levels of total GluR1 protein in both aged-unimpaired and aged-impaired rats were on par with the young rats (Fig. 2A and B, P > 0.05 vs young group). However, aged-impaired rats have lower levels of surface GluR1 in CA1 region, relative to young rats and aged-unimpaired rats (Fig. 2C and D, P < 0.01). The surface expressions of GluR1 subunit in aged-unimpaired and young rats did not significantly differ from each other (P > 0.05). To confirm the specific change of surface GluR1 in aged-impaired rats, we further examined the phosphorylation levels of GluR1 at Ser845 and Ser831, which regulate synaptic trafficking of GluR1 [22], in the hippocampal CA1 tissue.

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239

G Model NSL 31146 1–6

ARTICLE IN PRESS Y.-J. Yang et al. / Neuroscience Letters xxx (2015) xxx–xxx

240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305

As shown in Fig. 2E–G, the phosphorylation levels of GluR1(Ser831) and GluR1(Ser845) in aged-unimpaired and young rats did not significantly differ from each other, while both the phosphorylated GluR1(Ser831) and GluR1(Ser845) in the hippocampus of aged-impaired rats were much lower than those in young and agedunimpaired rats (P < 0.05 or 0.01 vs young or aged-unimpaired group), providing additional evidence for reduced surface GluR1 expression in aged-impaired rats. Then we looked for the relationship between the surface GluR1 level and behavioral performance among rats in the aged cohort. As shown in Fig. 3A, a significantly negative correlation was found between the surface GluR1 level in the CA1 region and the escape latency in the learning phase (Pearson’s r = −0.8154, P < 0.01). In addition, greater decrease in surface GluR1 expression was also associated with worse performance in the probe trial (Fig. 3B; Pearson’s r = 0.8355, P < 0.01). The results indicate that the lower the expression of surface GluR1 in CA1 region, the worse the cognitive function in 24-month-old SD rats. In this study, we have demonstrated that aged rats that are cognitively impaired showed significant decrease in surface GluR1 expression in hippocampal CA1 region compared to young rats and aged rats with preserved cognition. The index of the cognitive ability in aged rats positively correlated with the surface GluR1 level in CA1 region. That is, a lower surface GluR1 level in CA1 region is associated with worse ability in spatial learning and memory. Therefore, surface GluR1 level might be a key influencing factor of the individual differences in cognitive aging. Surface insertion of GluR1-containing AMPARs is required for N-methyl-d-aspartic acid receptors (NMDARs)-dependent LTP [8], the cellular model of learning and memory. Previous studies have demonstrated that the induction of NMDARs-LTP was reduced in aged rats and LTP magnitude was correlated with individual cognitive performance of rat [3,24]. Our result that surface GluR1 expression was selectively reduced in the hippocampus of agedimpaired rats was consistent with this eletrophysiological result. The surface insertion of GluR1-containing AMPARs requires the activations of calcium-dependent protein kinases such as CaMKII, PKC and PKA, and subsequent phosphorylations of GluR1 at Ser845 (PKA site) and Ser831 (PKC/CaMKII site) [6,8,22]. In present study, we found that the phosphorylation levels of GluR1 at Ser845 and Ser831 sites were significantly decreased in the hippocampus of aged-impaired rats, confirming the specific change of surface GluR1 in aged-impaired rats. In addition, results from Zeng et al. [24] that the phosphorylation levels of CaMKII and GluR1 were significantly reduced in the hippocampus of aged-impaired rats also supported our present finding. However, the mechanism of reduced surface GluR1 expression in the hippocampus of aged-impaired rat is unclear. Because AMPARs themselves lack motor do mains, the receptors must associate with protein partners that assist in their trafficking [6]. Stargazin, the founding member of the transmembrane AMPAR regulatory protein (TARP) family, has emerged as the principal determinant of AMPARs surface expression. Physiologically, stargazin is S-nitrosylated by NO and the S-nitrosylation of stargazin will increase its binding to the GluR1 subunit, causing increased surface expression of AMPARs [18]. Previous studies have shown that, compared to aged-unimpaired rats, aged-impaired rats exhibited more pronounced decrease in neuronal nitric oxide synthase activity and nitrite level in the hippocampus [11]. Furthermore, the old rats that exhibited strikingly decreased phosphorylation of GluR1 also displayed reduced expression of stargazin in the hippocampus [9]. Thus, we postulated that reduced NO and sequent downregulation of S-nitrosylation of stargazin might be a key contributor for the reduced surface GluR1 expression and cognitive decline in aged individuals. However, this hypothesis needs to be clarified in further investigations.

5

In conclusion, our results suggest that cognitive impairments with aging is associated with reduced surface GluR1 expression in the hippocampal CA1 region in old rats. This finding might account for the individual differences in cognitive aging and suggests that promoting surface insertion of GluR1-containing AMPARs could be a promising new strategy for the treatment of cognitive deficits associated with aging. Acknowledgments This work was supported by grants from the Natural Science Q3 Foundation of Jiangxi Province of China (NO. 20142BAB215028 and 20122BAB215035). It was also supported by start grant to Dr. Yang from Jiangxi Mental Hospital. References [1] M.M. Adams, L. Shi, M.C. Linville, M.E. Forbes, A.B. Long, C. Bennett, I.G. Newton, C.S. Carter, W.E. Sonntag, D.R. Riddle, J.K. Brunso-Bechtold, Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability, Exp. Neurol. 211 (2008) 141–149. [2] N. Andres, M.J. Rodriguez, C. Andrade, W. Rowe, R. Quirion, N. Mahy, Increase in AMPA receptors in aged memory-impaired rats is not associated with increase in monoamine oxidase B levels, Neuroscience 101 (2000) 807–810. [3] K. Boric, P. Munoz, M. Gallagher, A. Kirkwood, Potential adaptive function for altered long-term potentiation mechanisms in aging hippocampus, J. Neurosci. 28 (2008) 8034–8039. [4] A.C. Boudreau, M.E. Wolf, Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens, J. Neurosci. 25 (2005) 9144–9151. [5] S.N. Burke, C.A. Barnes, Neural plasticity in the ageing brain, Nat. Rev. Neurosci. 7 (2006) 30–40. [6] V.A. Derkach, M.C. Oh, E.S. Guire, T.R. Soderling, Regulatory mechanisms of AMPA receptors in synaptic plasticity, Nat. Rev. Neurosci. 8 (2007) 101–113. [7] F.H. Gage, A. Bjorklund, Cholinergic septal grafts into the hippocampal formation improve spatial learning and memory in aged rats by an atropine-sensitive mechanism, J. Neurosci. 6 (1986) 2837–2847. [8] Y. Hayashi, S.H. Shi, J.A. Esteban, A. Piccini, J.C. Poncer, R. Malinow, Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction, Science 287 (2000) 2262–2267. [9] M.P. Kelly, W. Adamowicz, S. Bove, A.J. Hartman, A. Mariga, G. Pathak, V. Reinhart, A. Romegialli, R.J. Kleiman, Select 3’,5’-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain, Cell. Signal. 26 (2014) 383–397. [10] M. Kollen, A. Stephan, A. Faivre-Bauman, C. Loudes, P.M. Sinet, J. Alliot, J.M. Billard, J. Epelbaum, P. Dutar, A. Jouvenceau, Preserved memory capacities in aged Lou/C/Jall rats, Neurobiol. Aging 31 (2010) 129–142. [11] A. Law, J. O’Donnell, S. Gauthier, R. Quirion, Neuronal and inducible nitric oxide synthase expressions and activities in the hippocampi and cortices of young adult, aged cognitively unimpaired, and impaired Long-Evans rats, Neuroscience 112 (2002) 267–275. [12] H.K. Lee, S.S. Min, M. Gallagher, A. Kirkwood, NMDA receptor-independent long-term depression correlates with successful aging in rats, Nat. Neurosci. 8 (2005) 1657–1659. [13] R.C. Malenka, M.F. Bear, LTP and LTD: an embarrassment of riches, Neuron 44 (2004) 5–21. [14] C. Menard, H. Herzog, C. Schwarzer, R. Quirion, Possible role of dynorphins in Alzheimer’s disease and age-related cognitive deficits, Neurodegener. Dis. 13 (2014) 82–85. [15] D. Mitsushima, K. Ishihara, A. Sano, H.W. Kessels, T. Takahashi, Contextual learning requires synaptic AMPA receptor delivery in the hippocampus, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 12503–12508. [16] D. Reisel, D.M. Bannerman, W.B. Schmitt, R.M. Deacon, J. Flint, T. Borchardt, P.H. Seeburg, J.N. Rawlins, Spatial memory dissociations in mice lacking GluR1, Nat. Neurosci. 5 (2002) 868–873. [17] D. Schulz, O.A. Sergeeva, E. Ianovskii, H.J. Luhmann, H.L. Haas, J.P. Huston, Behavioural parameters in aged rats are related to LTP and gene expression of ChAT and NMDA-NR2 subunits in the striatum, Eur. J. Neurosci. 19 (2004) 1373–1383. [18] B. Selvakumar, R.L. Huganir, S.H. Snyder, S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 16440–16445. [19] A.M. Stranahan, R.P. Haberman, M. Gallagher, Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats, Cereb. Cortex 21 (2011) 392–400. [20] Y.J. Yang, Y.K. Li, W. Wang, J.G.B. Wan, Yu, M.Z. Wang, B. Hu, Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia, Pharmacol. Biochem. Behav. 122 (2014) 30–36.

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

306 307 308 309 310 311 312

313

314 315 316 317

318

319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381

G Model NSL 31146 1–6 6 382 383 384 385 386 387

ARTICLE IN PRESS Y.-J. Yang et al. / Neuroscience Letters xxx (2015) xxx–xxx

[21] Y.J. Yang, P.F. Wu, L.H. Long, D.F. Yu, W.N. Wu, Z.L. Hu, H. Fu, N. Xie, Y. Jin, L. Ni, J.Z. Wang, F. Wang, J.G. Chen, Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function, Aging Cell 9 (2010) 709–721. [22] S.M. Yong, M.L. Lim, C.M. Low, B.S. Wong, Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice, Sci. Rep. 4 (2014) 6580.

[23] D.F. Yu, P.F. Wu, H. Fu, J. Cheng, Y.J. Yang, T. Chen, L.H. Long, J.G. Chen, F. Wang, Aging-related alterations in the expression and distribution of GluR2 and PICK1 in the rat hippocampus, Neurosci. Lett. 497 (2011) 42–45. [24] Y. Zeng, F. Lv, L. Li, H. Yu, M. Dong, Q. Fu, 7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats, J. Neurochem. 122 (2012) 800–811.

Please cite this article in press as: Y.-J. Yang, et al., Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.030

388 389 390 391 392 393

Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats.

Individual differences in cognitive aging exist in humans and in rodent populations, yet the underlying mechanisms remain largely unclear. Activity-de...
772KB Sizes 0 Downloads 9 Views