Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice

Laura Leung, Yaisa Andrews-Zwilling, Seo Yeon Yoon, Sachi Jain, Karen Ring, Jessica Dai, Max Mu Wang, Leslie Tong, David Walker, Yadong Huang, Laura Leung, Yaisa Andrews-Zwilling, Seo Yeon Yoon, Sachi Jain, Karen Ring, Jessica Dai, Max Mu Wang, Leslie Tong, David Walker, Yadong Huang

Abstract

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Aged female mice show apoE4-induced…
Figure 1. Aged female mice show apoE4-induced spatial learning and memory deficits, but male mice do not.
A, 16-month old male and female apoE3-KI or apoE4-KI mice (n = 10−12 mice per group) were tested in the Morris water maze. Points represent averages of daily trials. H, hidden platform day (2 trials/session, 2 sessions/day); H0, first trial on H1; V, visible platform day (2 trials/session, 2 sessions/day). Escape latency (y-axis) indicates time to reach the target. In the hidden platform days, latencies of all groups of mice were analyzed and compared by repeated measures ANOVA and Bonferroni post-hoc test. Female apoE4-KI mice learned significantly slower than female apoE3-KI mice (repeated-measures ANOVA and Bonferroni post-hoc test, p<0.01) . Male apoE3-KI and apoE4-KI mice performed at a similar level to female apoE3-KI mice. B, Swim speed was not different among the various groups of mice. C, D, Probe 1 trials of female (C, n = 10−12) and male (D, n = 7−9) apoE3-KI or apoE4-KI mice were performed 24 h after the last hidden day platform training. E, F, Probe 2 trials of female (E, n = 10−12) and male (F, n = 7−9) apoE3-KI or apoE4-KI mice were performed 72 h after the last hidden day platform training. Percentage time spent in the target quadrant versus the time spent in any of the three non-target quadrants differed in all groups except for female apoE4-KI mice. **p<0.01, ***p<0.001 (t-test).
Figure 2. ApoE-KI mice exhibit basal sex…
Figure 2. ApoE-KI mice exhibit basal sex differences in hilar GABAergic interneurons at 1-month of age.
A–D, Representative images (200x) of anti-GAD67-immunostained sections of the hilus of female apoE3-KI (A), female apoE4-KI (B), male apoE3-KI (C), and male apoE4-KI (D) mice at 1 month of age. E–H, Representative images (200x) of anti-somatostatin-immunostained sections of the hilus of female apoE3-KI (E), female apoE4-KI (F), male apoE3-KI (G), and male apoE4-KI (H) mice at 1 month of age. I–L, Representative images (200x) of anti-NPY-immunostained sections of the hilus of female apoE3-KI (I), female apoE4-KI (J), male apoE3-KI (K), and male apoE4-KI (L) mice at 1 month of age. M–P, Representative images (200x) of anti-parvalbumin-immunostained sections of the hilus of female apoE3-KI (M), female apoE4-KI (N), male apoE3-KI (O), and male apoE4-KI (P) mice at 1 month of age. Q–T, Quantification of hilar GABAergic interneurons positive for GAD67 (Q), somatostatin (R), neuropeptide Y (S), or parvalbumin (T) in female and male apoE-KI mice at 1 month of age (n = 6–12 per group). Results in histograms are presented as the total number of positive cells counted per brain. Male apoE-KI mice have significantly fewer hilar GABAergic interneurons than female apoE-KI mice at 1 month of age by t-test, **p<0.01; ***p<0.001.
Figure 3. GAD67-immunopositive hilar GABAergic interneuron numbers…
Figure 3. GAD67-immunopositive hilar GABAergic interneuron numbers change as a function of age, sex, and apoE isoforms.
A, B, Quantification of hilar GABAergic interneurons positive for GAD67 in female (A) or male (B) apoE-KI mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). Results in histograms are presented as the total number of positive cells counted per brain. Female apoE-KI mice show an apoE isoform-dependent and age-dependent effect, but no interaction between the two variables was observed by 2-way ANOVA . *p<0.05; **p<0.01 in female apoE4-KI mice compared to female apoE3-KI mice at the same age (post-hoc Bonferroni test). Male apoE-KI mice also show an apoE isoform–dependent effect, and further exhibit an interaction between the two variables by 2-way ANOVA, *p<0.05 (post-hoc Bonferroni test). C, D, Quantification of GAD67-positive hilar interneurons in female and male apoE3-KI (C) or apoE4-KI (D) mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). ApoE3-KI mice show a sex-dependent effect, with interaction between sex and age by 2-way ANOVA. ApoE4-KI mice show an age-dependent, but sex-independent, effect with interaction between the two variables by 2-way ANOVA. *p<0.05; **p<0.01; ***p<0.001 in male apoE-KI mice compared to their female counterparts (post-hoc Bonferroni test). E–H, Representative images (200x) of anti-GAD67-immunostained sections of the hilus of female apoE3-KI (E), female apoE4-KI (F), male apoE3-KI (G), and male apoE4-KI (H) mice at 16 months of age. I, J, Escape latency in hidden platform days 1−5 correlated inversely with the number of GAD67-positive hilar interneurons in female apoE4-KI mice (J, n = 12) but not female apoE3-KI mice (I, n = 10) at 16 months of age .
Figure 4. Age- and sex-dependent effects on…
Figure 4. Age- and sex-dependent effects on numbers of hilar GABAergic interneurons in wild-type mice.
A–D, Hilar GABAergic interneurons positive for GAD67 (A), somatostatin (B), neuropeptide Y (C), and parvalbumin (D) in female and male wild-type mice at 1, 6, 12, and 16 months of age (n = 6−8 mice per group). Results in histograms are presented as the total number of positive cells counted per brain. **p<0.01; ***p<0.005 (post-hoc Bonferroni test).
Figure 5. Age- and sex-dependent effects on…
Figure 5. Age- and sex-dependent effects on numbers of somatostatin-immunopositive hilar GABAergic interneurons in apoE-KI mice.
A, B, Histograms showing the total number of somatostatin-positive hilar GABAergic interneurons in female (A) or male (B) apoE3-KI or apoE4-KI mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). Female apoE-KI mice show an apoE isoform-dependent and age-dependent effect, but no interaction between the two variables by 2-way ANOVA . Male apoE-KI mice demonstrate an age-dependent effect, but no apoE isoform–dependent effects. No interaction was detected between the two variables. *p<0.05; ***p<0.005 in female apoE4-KI mice compared to female apoE3-KI mice at the same age (post-hoc Bonferroni test). C, D, Quantification of somatostatin-positive hilar GABAergic interneurons in female and male apoE3-KI (C) or apoE4-KI (D) mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). ApoE3-KI mice have age-dependent and sex-independent effects, whereas apoE4-KI mice show an age-independent and sex-dependent effect. Both apoE genotypes show an interaction between age and sex by 2-way ANOVA. *p<0.05; ***p<0.001 in male apoE-KI mice compared to female apoE-KI mice at the same age (post-hoc Bonferroni test). E–H, Representative images (200x) of somatostatin-immunostained hilar sections of female apoE3-KI (E), female apoE4-KI (F), male apoE3-KI (G), and male apoE4-KI (H) mice at 16 months of age. I, J, Escape latency in hidden platform days 1−5 correlated inversely with the number of somatostatin-positive hilar interneurons in female apoE4-KI mice (I, n = 12) but not female apoE3-KI mice (J, n = 10) at 16 months of age .
Figure 6. Age- and sex-dependent effects on…
Figure 6. Age- and sex-dependent effects on numbers of neuropeptide Y-immunopositive hilar GABAergic interneurons in apoE-KI mice.
A, B, Histograms showing the total number of hilar GABAergic interneurons immunopositive for neuropeptide Y in female (A) or male (B) apoE-KI mice at the identified ages. Female and male apoE-KI mice show that NPY-positive interneuron levels are similarly apoE genotype-independent, but are age-dependent in opposite directions, whereby NPY-positive interneurons decrease and increase with age in females and males, respectively. There was no interaction between the two variables (by 2-way ANOVA) for either sex. C, D Quantification of NPY-positive hilar interneurons in female and male apoE3-KI (C) and apoE4-KI (D) mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). Both genotypes show age-independent, but sex-dependent, effects on NPY-positive interneurons by 2-way ANOVA. *p<0.05; **p<0.01; ***p<0.001 in male apoE-KI mice compared to female apoE-KI mice at the same age (post-hoc Bonferroni test). E–H, Representative images (200x) of neuropeptide Y–immunostained sections of the hilus of female apoE3-KI (E), female apoE4-KI (F), male apoE3-KI (G), and male apoE4-KI (H) mice at 16 months of age.
Figure 7. Age- and sex-dependent effects on…
Figure 7. Age- and sex-dependent effects on numbers of parvalbumin-immunopositive hilar GABAergic interneurons in apoE-KI mice.
A, B, Histograms showing the total number of hilar GABAergic interneurons immunopositive for parvalbumin (PV) in female (A) or male (B) apoE-KI mice at the identified ages. Female apoE-KI mice show apoE genotype-independent and age-dependent effects, but no interaction between the two variables by 2-way ANOVA. Male apoE-KI mice show an age-dependent effect but no apoE genotype-dependent effect. There was no interaction between the two variables by 2-way ANOVA. C, D, Quantification of parvalbumin-positive hilar interneurons in female and male apoE3-KI (C) and apoE4-KI (D) mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). Both apoE3-KI and apoE4-KI mice show an effect of sex on parvalbumin interneuron numbers. An interaction between age and sex was present for both apoE genotypes (2-way ANOVA). *p<0.05; **p<0.01; ***p<0.001 in male apoE-KI mice compared to female apoE-KI mice at the same age (post-hoc Bonferroni test). E–H, Representative images (200x) of hilar sections stained with anti-parvalbumin antibodies. Shown are female apoE3-KI (E), female apoE4-KI (F), male apoE3-KI (G), and male apoE4-KI (H) mice at 16 months of age.
Figure 8. The balance between inhibitory and…
Figure 8. The balance between inhibitory and excitatory hilar interneurons depends on age, sex, and apoE isoform.
A–D, Histograms showing the number of hilar neurons positive for GAD67 (purple), calretinin (grey), or NeuN (blue) in female (A, B) and male (C, D) apoE3-KI (A, C) or apoE4-KI (B, D) mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). E-F, Ratios of GAD67-positive interneurons to calretinin-positive mossy cells in the hilus of the dentate gyrus of female (E) and male (F) apoE-KI mice at 1, 3, 6, 12, and 16 months of age (n = 6−12 mice per group). *p<0.05 (t-test).
Figure 9. GABAergic interneurogenesis in the hilus…
Figure 9. GABAergic interneurogenesis in the hilus is sex-dependent in aged apoE-KI mice.
A, Total numbers of BrdU and GABA double-positive cells in the hilus of female and male apoE-KI mice at 16 months of age were determined 1 month after BrdU injection. Values are mean ± SE (n = 6−8 mice per group). *p<0.05 in 16-month-old male apoE4-KI mice compared to their female counterparts (post-hoc Bonferroni test); **p<0.01 in older male apoE3-KI mice compared to their female counterparts at the same age (post-hoc Bonferroni test). B, D, Images of the hilus of 16-month-old male apoE3-KI mice stained with anti-BrdU (red) and anti-GABA (green) collected 1 month after BrdU injection (magnification: B, 100x; D, 200x). C, E, Images of the hilus of 16-month-old male apoE4-KI mice stained with anti-BrdU (red) and anti-GABA (green) collected 1 month after BrdU injection (magnification: C, 100x; E, 200x).

References

    1. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353–356.
    1. Perrin RJ, Fagan AM, Holtzman DM (2009) Multimodal techniques for diagnosis and prognosis of Alzheimer's disease. Nature 461: 916–922.
    1. Vas CJ, Pinto C, Panikker D, Noronha S, Deshpande N, et al. (2001) Prevalence of dementia in an urban Indian population. Int Psychogeriatr 13: 439–450.
    1. Fratiglioni L, Grut M, Forsell Y, Viitanen M, Grafstrom M, et al. (1991) Prevalence of Alzheimer's disease and other dementias in an elderly urban population: relationship with age, sex, and education. Neurology 41: 1886–1892.
    1. Wang W, Wu S, Cheng X, Dai H, Ross K, et al. (2000) Prevalence of Alzheimer's disease and other dementing disorders in an urban community of Beijing, China. Neuroepidemiology 19: 194–200.
    1. Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, et al. (1999) Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology 53: 1992–1997.
    1. Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, et al. (1997) Very old women at highest risk of dementia and Alzheimer's disease: incidence data from the Kungsholmen Project, Stockholm. Neurology 48: 132–138.
    1. Gao S, Hendrie HC, Hall KS, Hui S (1998) The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55: 809–815.
    1. Payami H, Montee K, Grimslid H, Shattuc S, Kaye J (1996) Increased risk of familial late-onset Alzheimer's disease in women. Neurology 46: 126–129.
    1. Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7: 477–484.
    1. Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, et al. (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62: 685–691.
    1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921–923.
    1. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, et al. (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90: 1977–1981.
    1. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama 278: 1349–1356.
    1. Mortensen EL, Hogh P (2001) A gender difference in the association between APOE genotype and age-related cognitive decline. Neurology 57: 89–95.
    1. Beydoun MA, Boueiz A, Abougergi MS, Kitner-Triolo MH, Beydoun HA, et al. (2010) Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia, cognitive impairment, and decline. Neurobiol Aging 33: 720–731.
    1. Baum LW (2005) Sex, hormones, and Alzheimer's disease. J Gerontol A Biol Sci Med Sci 60: 736–743.
    1. Brookmeyer R, Corrada MM, Curriero FC, Kawas C (2002) Survival following a diagnosis of Alzheimer disease. Arch Neurol 59: 1764–1767.
    1. Payami H, Montee KR, Kaye JA, Bird TD, Yu CE, et al. (1994) Alzheimer's disease, apolipoprotein E4, and gender. Jama 271: 1316–1317.
    1. Raber J, Wong D, Buttini M, Orth M, Bellosta S, et al. (1998) Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A 95: 10914–10919.
    1. Raber J, Wong D, Yu GQ, Buttini M, Mahley RW, et al. (2000) Apolipoprotein E and cognitive performance. Nature 404: 352–354.
    1. Pfankuch T, Rizk A, Olsen R, Poage C, Raber J (2005) Role of circulating androgen levels in effects of apoE4 on cognitive function. Brain Res 1053: 88–96.
    1. McEwen BS (1997) Hormones as regulators of brain development: life-long effects related to health and disease. Acta Paediatr Suppl 422: 41–44.
    1. Romeo RD, Waters EM, McEwen BS (2004) Steroid-induced hippocampal synaptic plasticity: sex differences and similarities. Neuron Glia Biol 1: 219–229.
    1. Hajszan T, Milner TA, Leranth C (2007) Sex steroids and the dentate gyrus. Prog Brain Res 163: 399–415.
    1. Raber J, Bongers G, LeFevour A, Buttini M, Mucke L (2002) Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci 22: 5204–5209.
    1. Acevedo S, Gardell L, Bradley SR, Piu F, Raber J (2008) Selection androgen receptor modulators antagonize apolipoprotein E4-induced cognitive impairments. Lett Drug Des Discov 5: 271–276.
    1. Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, et al. (2010) Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30: 13707–13717.
    1. Andrews-Zwilling Y, Gillespie AK, Kravitz AV, Nelson AB, Devidze N, et al. (2012) Hilar GABAergic interneuron activity controls spatial learning and memory retrieval. PloS ONE 7: e40555.
    1. Sullivan PM, Mace BE, Maeda N, Schmechel DE (2004) Marked regional differences of brain human apolipoprotein E expression in targeted replacement mice. Neuroscience 124: 725–733.
    1. Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, et al. (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272: 17972–17980.
    1. McKinney TD (1972) Estrous cycle in house mice: effects of grouping, preputial gland odors, and handling. J Mammal 53: 391–393.
    1. Takahashi H, Brasnjevic I, Rutten BP, Van Der Kolk N, Perl DP, et al. (2010) Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer's disease. Brain Struct Funct 214: 145–160.
    1. Ramos B, Baglietto-Vargas D, del Rio JC, Moreno-Gonzalez I, Santa-Maria C, et al. (2006) Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer's disease. Neurobiol Aging 27: 1658–1672.
    1. Fukuda T, Aika Y, Heizmann CW, Kosaka T (1998) GABAergic axon terminals at perisomatic and dendritic inhibitory sites show different immunoreactivities against two GAD isoforms, GAD67 and GAD65, in the mouse hippocampus: a digitized quantitative analysis. J Comp Neurol 395: 177–194.
    1. Fukuda T, Heizmann CW, Kosaka T (1997) Quantitative analysis of GAD65 and GAD67 immunoreactivities in somata of GABAergic neurons in the mouse hippocampus proper (CA1 and CA3 regions), with special reference to parvalbumin-containing neurons. Brain Res 764: 237–243.
    1. Jinno S, Kosaka T (2009) Neuronal circuit-dependent alterations in expression of two isoforms of glutamic acid decarboxylase in the hippocampus following electroconvulsive shock: A stereology-based study. Hippocampus 19: 1130–1141.
    1. West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14: 275–285.
    1. West MJ (2001) Design based stereological methods for estimating the total number of objects in histological material. Folia Morphol (Warsz) 60: 11–19.
    1. West MJ (2002) Design-based stereological methods for counting neurons. Prog Brain Res 135: 43–51.
    1. Veliskova J, Velisek L (2007) Beta-estradiol increases dentate gyrus inhibition in female rats via augmentation of hilar neuropeptide Y. J Neurosci. 27: 6054–6063.
    1. Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, et al. (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A 100: 10966–10971.
    1. Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M (2010) Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 35: 1016–1025.
    1. Murray AJ, Sauer JF, Riedel G, McClure C, Ansel L, et al. (2011) Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nat Neurosci 14: 297–299.
    1. Amaral DG, Scharfman HE, Lavenex P (2007) The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res 163: 3–22.
    1. Myers CE, Scharfman HE (2009) A role for hilar cells in pattern separation in the dentate gyrus: a computational approach. Hippocampus 19: 321–337.
    1. Castellano C, Introini-Collison IB, McGaugh JL (1993) Interaction of beta-endorphin and GABAergic drugs in the regulation of memory storage. Behav Neural Biol 60: 123–128.
    1. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, et al. (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22: 5572–5580.
    1. Hu JH, Ma YH, Jiang J, Yang N, Duan SH, et al. (2004) Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1). Neuroreport 15: 9–12.
    1. Davies P, Katzman R, Terry RD (1980) Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementia. Nature 288: 279–280.
    1. Hardy J, Cowburn R, Barton A, Reynolds G, Dodd P, et al. (1987) A disorder of cortical CABAergic innervation in Alzheimer's disease. Neurosi Lett 73: 192–196.
    1. Seidl R, Cairns N, Singewald N, Kaehler ST, Lubec G (2001) Differences between GABA levels in Alzheimer's disase and Down syndrome with Alzheimer-like neuropathology. Naunyn Schmiedeberg Arch Pharmacol 363: 139–145.
    1. Bareggi SR, Franceschi M, Bonini L, Zecca L, Smirne S (1982) Decreased CSF concentrations of homovanillic acid and γ-aminobutyric acid in Alzheimer's disease. Age- or disease-related modifications? Arch Neurol 39: 709–712.
    1. Zimmer R, Teelken AW, Trieling WB, Weber W, Weihmayr T, et al. (1984) γ-Aminobutyric acid and homovanillic acid concentration in the CSF of patients with senile dementia of Alzheimer's type. Arch Neurol 41: 602–604.
    1. Grouselle D, Winsky-Sommerer R, David JP, Delacourte A, Dournaud P, et al. (1998) Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele. Neuroscience Letters 255: 21–24.
    1. Vepsalainen S, Helisalmi S, Koivisto AM, Tapaninen T, Hiltunen M, et al. (2007) Somatostatin genetic variants mmodify the risk for Alzheimer's disease among Finnish patients. J Neurol 254: 1504–1508.
    1. Xue S, Jia L, Jia J (2009) Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population. Neurosci Lett 465: 181–183.
    1. Shi J, Cai Y, Liu G, Gong N, Liu Z, et al... (2012) Enhanced learning and memory in GAT1 heterozygous mice. Acta Biochim Biophys Sin (Shanghai).
    1. Tokita K, Inoue T, Yamazaki S, Wang F, Yamaji T, et al. (2005) FK962, a novel enhancer of somatostatin release, exerts cognitive-enhancing actions in rats. Eur J Pharmacol 527: 111–120.
    1. Beatty WW (1979) Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences. Horm Behav 12: 112–163.
    1. Clancy AN, Bonsall RW, Michael RP (1992) Immunohistochemical labeling of androgen receptors in the brain of rat and monkey. Life Sci 50: 409–417.
    1. McAbee MD, DonCarlos LL (1998) Ontogeny of region-specific sex differences in androgen receptor messenger ribonucleic acid expression in the rat forebrain. Endocrinology 139: 1738–1745.
    1. Tabori NE, Stewart LS, Znamensky V, Romeo RD, Alves SE, et al. (2005) Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation. Neuroscience 130: 151–163.
    1. Luine VN (1997) Steroid Hormone Modulation of Hippocampal Dependent Spatial Memory. Stress 2: 21–36.
    1. Fillit H, Luine V (1997) The neurobiology of gonadal hormones and cognitive decline in late life. Maturitas 26: 159–164.
    1. Loy R, Gerlach JL, McEwen BS (1988) Autoradiographic localization of estradiol-binding neurons in the rat hippocampal formation and entorhinal cortex. Brain Res 467: 245–251.
    1. Milner TA, McEwen BS, Hayashi S, Li CJ, Reagan LP, et al. (2001) Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol 429: 355–371.
    1. Weiland NG, Orikasa C, Hayashi S, McEwen BS (1997) Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats. J Comp Neurol 388: 603–612.
    1. Shughrue PJ, Merchenthaler I (2000) Evidence for novel estrogen binding sites in the rat hippocampus. Neuroscience 99: 605–612.
    1. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6: 347–470.
    1. Hilke S, Holm L, Man K, Hokfelt T, Theodorsson E (2009) Rapid change of neuropeptide Y levels and gene-expression in the brain of ovariectomized mice after administration of 17beta-estradiol. Neuropeptides 43: 327–332.
    1. Weiland NG (1992) Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus. Endocrinology 131: 2697–2702.
    1. Nakamura NH, Rosell DR, Akama KT, McEwen BS (2004) Estrogen and ovariectomy regulate mRNA and protein of glutamic acid decarboxylases and cation-chloride cotransporters in the adult rat hippocampus. Neuroendocrinology 80: 308–323.
    1. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, et al. (2002) Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87: 589–598.
    1. Gray A, Feldman HA, McKinlay JB, Longcope C (1991) Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 73: 1016–1025.
    1. Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT (2003) Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 149: 583–589.
    1. Naftolin F, Ryan KJ, Davies IJ, Petro Z, Kuhn M (1975) The formation and metabolism of estrogens in brain tissues. Adv Biosci 15: 105–121.
    1. Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I (2002) Estradiol in elderly men. Aging Male 5: 98–102.
    1. Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC (1974) Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab 38: 476–479.
    1. Stoffel-Wagner B, Watzka M, Steckelbroeck S, Schwaab R, Schramm J, et al. (1998) Expression of CYP19 (aromatase) mRNA in the human temporal lobe. Biochem Biophys Res Commun 244: 768–771.
    1. Huang Y (2010) Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol Med 16: 287–294.
    1. Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148: 1204–1222.
    1. Mendez MF, Catanzaro P, Doss RC, R AR, Frey WH, 2nd (1994) Seizures in Alzheimer's disease: clinicopathologic study. J Geriatr Psychiatry Neurol 7: 230–233.
    1. Larner AJ (2010) Epileptic seizures in AD patients. Neuromolecular Med 12: 71–77.
    1. Austin JE, Buckmaster PS (2004) Recurrent excitation of granule cells with basal dendrites and low interneuron density and inhibitory postsynaptic current frequency in the dentate gyrus of macaque monkeys. J Comp Neurol 476: 205–218.
    1. Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, et al. (2005) Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci 8: 1059–1068.
    1. Kobayashi M, Buckmaster PS (2003) Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci 23: 2440–2452.
    1. Lloyd KG, Bossi L, Morselli PL, Munari C, Rougier M, et al. (1986) Alterations of GABA-mediated synaptic transmission in human epilepsy. Adv Neurol 44: 1033–1044.
    1. Zappone CA, Sloviter RS (2004) Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons. J Neurosci 24: 853–864.
    1. Gill DA, Ramsay SL, Tasker RA (2010) Selective reductions in subpopulations of GABAergic neurons in a developmental rat model of epilepsy. Brain Res 1331: 114–123.
    1. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, et al. (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55: 697–711.
    1. Medina AE, Manhaes AC, Schmidt SL (2001) Sex differences in sensitivity to seizures elicited by pentylenetetrazol in mice. Pharmacol Biochem Behav 68: 591–596.
    1. Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66: 435–440.
    1. Hunter JM, Cirrito JR, Restivo JL, Kinley RD, Sullivan PM, et al. (2012) Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice. Brain Res 1467: 120–132.

Source: PubMed

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