Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases

Nature Neuroscience volume 25, pages 180–190 (2022)Cite this article

Subjects

Abstract

Multiple studies indicate that adult male rodents perform better than females on spatial problems and have a lower threshold for long-term potentiation (LTP) of hippocampal CA3-to-CA1 synapses. We report here that, in rodents, prepubescent females rapidly encode spatial information and express low-threshold LTP, whereas age-matched males do not. The loss of low-threshold LTP across female puberty was associated with three inter-related changes: increased densities of α5 subunit-containing GABAARs at inhibitory synapses, greater shunting of burst responses used to induce LTP and a reduction of NMDAR-mediated synaptic responses. A negative allosteric modulator of α5-GABAARs increased burst responses to a greater degree in adult than in juvenile females and markedly enhanced both LTP and spatial memory in adults. The reasons for the gain of functions with male puberty do not involve these mechanisms. In all, puberty has opposite consequences for plasticity in the two sexes, albeit through different routes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sex differences in adult rat LTP thresholds are reversed before puberty.
Fig. 2: Adult sex differences in spatial learning are reversed before puberty.
Fig. 3: Theta burst responses, feed-forward inhibition and NMDAR-mediated synaptic potentials differ between prepubescent and postpubescent female rats.
Fig. 4: Synaptic levels of GABAAR subunits in prepubescent versus postpubescent female rats.
Fig. 5: A NAM (L655,708) of the α5-GABAAR subunit increases theta burst responses and facilitates LTP in adult females.
Fig. 6: LTP induction in prepubescent female rats is dependent on activation of ERα.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available in this manuscript and the Supplementary Information. Source data are provided with this paper.

Code availability

Single and theta burst parameters for field electrophysiology were analyzed using code available at https://github.com/cdcox/Theta-burst-analyzer-for-Le-et-al. Code for FDT analysis is available upon reasonable request. The use of the FDT code is strictly prohibited without a licensing agreement from the University of California, Irvine.

References

  1. Andreano, J. M. & Cahill, L. Sex influences on the neurobiology of learning and memory. Learn. Mem. 16, 248–266 (2009).

    Article  PubMed  Google Scholar 

  2. Koss, W. A. & Frick, K. M. Sex differences in hippocampal function. J. Neurosci. Res. 95, 539–562 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Tascón, L. et al. Sex differences in spatial memory: comparison of three tasks using the same virtual context. Brain Sci. 11, 757 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bocchi, A. et al. The role of gender and familiarity in a modified version of the almeria boxes room spatial task. Brain Sci. 11, 681 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Voyer, D., Voyer, S. D. & Saint-Aubin, J. Sex differences in visual-spatial working memory: a meta-analysis. Psychon. Bull. Rev. 24, 307–334 (2017).

    Article  PubMed  Google Scholar 

  6. Voyer, D., Voyer, S. & Bryden, M. P. Magnitude of sex differences in spatial abilities: a meta-analysis and consideration of critical variables. Psychol. Bull. 117, 250–270 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Seurinck, R., Vingerhoets, G., de Lange, F. P. & Achten, E. Does egocentric mental rotation elicit sex differences? Neuroimage 23, 1440–1449 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Yagi, S. & Galea, L. A. M. Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology 44, 200–213 (2019).

    Article  PubMed  Google Scholar 

  9. Jones, C. M., Braithwaite, V. A. & Healy, S. D. The evolution of sex differences in spatial ability. Behav. Neurosci. 117, 403–411 (2003).

    Article  PubMed  Google Scholar 

  10. Vierk, R. et al. Aromatase inhibition abolishes LTP generation in female but not in male mice. J. Neurosci. 32, 8116–8126 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hojo, Y. et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. Proc. Natl Acad. Sci. USA 101, 865–870 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Kato, A. et al. Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. Front. Neural Circuits 7, 149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tabatadze, N., Sato, S. M. & Woolley, C. S. Quantitative analysis of long-form aromatase mRNA in the male and female rat brain. PLoS ONE 9, e100628 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mukai, H. et al. Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim. Biophys. Acta 1800, 1030–1044 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Ooishi, Y. et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J. Steroid Biochem. Mol. Biol. 131, 37–51 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Wang, W. et al. Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus. J. Neurosci. 38, 7935–7951 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kight, K. E. & McCarthy, M. M. Androgens and the developing hippocampus. Biol. Sex. Differ. 11, 30 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Juraska, J. M. & Willing, J. Pubertal onset as a critical transition for neural development and cognition. Brain Res. 1654, 87–94 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Sisk, C. L. & Zehr, J. L. Pubertal hormones organize the adolescent brain and behavior. Front. Neuroendocrinol. 26, 163–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Baudry, M., Arst, D., Oliver, M. & Lynch, G. Development of glutamate binding sites and their regulation by calcium in rat hippocampus. Brain Res. 227, 37–48 (1981).

    Article  CAS  PubMed  Google Scholar 

  21. Muller, D., Oliver, M. & Lynch, G. Developmental changes in synaptic properties in hippocampus of neonatal rats. Brain Res. Dev. Brain Res. 49, 105–114 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Figurov, A., Pozzo-Miller, L. D., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Shen, H. et al. A critical role for α4βδ GABAA receptors in shaping learning deficits at puberty in mice. Science 327, 1515–1518 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith, S. S. The influence of stress at puberty on mood and learning: role of the α4βδ GABAA receptor. Neuroscience 249, 192–213 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Pattwell, S. S., Lee, F. S. & Casey, B. J. Fear learning and memory across adolescent development: hormones and behavior special issue: puberty and adolescence. Horm. Behav. 64, 380–389 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Romeo, R. D. Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development. J. Neuroendocrinol. 15, 1185–1192 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Larson, J. & Lynch, G. Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. Science 232, 985–988 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Barrett, R. M. et al. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory. Neuropsychopharmacology 36, 1545–1556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Inagaki, T., Gautreaux, C. & Luine, V. Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas. Horm. Behav. 58, 415–426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Boulware, M. I., Heisler, J. D. & Frick, K. M. The memory-enhancing effects of hippocampal estrogen receptor activation involve metabotropic glutamate receptor signaling. J. Neurosci. 33, 15184–15194 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bell, M. R. Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans. Endocrinology 159, 2596–2613 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Alger, B. E. & Nicoll, R. A. Feed-forward dendritic inhibition in rat hippocampal pyramidal cells studied in vitro. J. Physiol. 328, 105–123 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Larson, J. & Munkácsy, E. Theta-burst LTP. Brain Res. 1621, 38–50 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Ben-Ari, Y., Krnjević, K., Reiffenstein, R. J. & Reinhardt, W. Inhibitory conductance changes and action of γ-aminobutyrate in rat hippocampus. Neuroscience 6, 2445–2463 (1981).

    Article  CAS  PubMed  Google Scholar 

  35. Pacelli, G. J., Su, W. & Kelso, S. R. Activity-induced decrease in early and late inhibitory synaptic conductances in hippocampus. Synapse 7, 1–13 (1991).

    Article  CAS  PubMed  Google Scholar 

  36. Pacelli, G. J., Su, W. & Kelso, S. R. Activity-induced depression of synaptic inhibition during LTP-inducing patterned stimulation. Brain Res. 486, 26–32 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Larson, J. & Lynch, G. Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal θ-rhythm. Brain Res. 441, 111–118 (1988).

    Article  CAS  PubMed  Google Scholar 

  38. Rex, C. S. et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Seese, R. R. et al. Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. J. Neurosci. 33, 13441–13448 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schulz, J. M., Knoflach, F., Hernandez, M. C. & Bischofberger, J. Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABA. Nat. Commun. 9, 3576 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Davies, C. H., Starkey, S. J., Pozza, M. F. & Collingridge, G. L. GABA autoreceptors regulate the induction of LTP. Nature 349, 609–611 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Mott, D. D. & Lewis, D. V. Facilitation of the induction of long-term potentiation by GABAB receptors. Science 252, 1718–1720 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Sigel, E. & Steinmann, M. E. Structure, function, and modulation of GABAA receptors. J. Biol. Chem. 287, 40224–40231 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Collinson, N. et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor. J. Neurosci. 22, 5572–5580 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sieghart, W. & Sperk, G. Subunit composition, distribution and function of GABAA receptor subtypes. Curr. Top. Med. Chem. 2, 795–816 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Sur, C., Quirk, K., Dewar, D., Atack, J. & McKernan, R. Rat and human hippocampal α5 subunit-containing γ-aminobutyric AcidA receptors have α5β3γ2 pharmacological characteristics. Mol. Pharmacol. 54, 928–933 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Wainwright, A., Sirinathsinghji, D. J. & Oliver, K. R. Expression of GABAA receptor α5 subunit-like immunoreactivity in human hippocampus. Brain Res. Mol. Brain Res. 80, 228–232 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Mukherjee, J. et al. Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABA. Proc. Natl Acad. Sci. USA 114, 11763–11768 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Weiland, N. G. & Orchinik, M. Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus. Brain Res. Mol. Brain Res. 32, 271–278 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Herbison, A. E. & Fénelon, V. S. Estrogen regulation of GABAA receptor subunit mRNA expression in preoptic area and bed nucleus of the stria terminalis of female rat brain. J. Neurosci. 15, 2328–2337 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vastagh, C., Rodolosse, A., Solymosi, N. & Liposits, Z. Altered expression of genes encoding neurotransmitter receptors in GnRH neurons of proestrous mice. Front. Cell Neurosci. 10, 230 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Franco-Enzástiga, Ú. et al. Sex-dependent pronociceptive role of spinal α5-GABAA receptor and its epigenetic regulation in neuropathic rodents J. Neurochem. 156, 897–916 (2021).

  53. Spiegel, I. et al. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 157, 1216–1229 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sim, S. et al. Increased cell-intrinsic excitability induces synaptic changes in new neurons in the adult dentate gyrus that require Npas4. J. Neurosci. 33, 7928–7940 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shepard, R., Heslin, K., Hagerdorn, P. & Coutellier, L. Downregulation of Npas4 in parvalbumin interneurons and cognitive deficits after neonatal NMDA receptor blockade: relevance for schizophrenia. Transl. Psychiatry 9, 99 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Morgan, P. J., Bourboulou, R., Filippi, C., Koenig-Gambini, J. & Epsztein, J. Kv1.1 contributes to a rapid homeostatic plasticity of intrinsic excitability in CA1 pyramidal neurons in vivo. eLife 8, e49915 (2019).

  57. Monaghan, M. M., Trimmer, J. S. & Rhodes, K. J. Experimental localization of Kv1 family voltage-gated K+ channel α and β subunits in rat hippocampal formation. J. Neurosci. 21, 5973–5983 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dore, K., Aow, J. & Malinow, R. The emergence of NMDA receptor metabotropic function: insights from imaging. Front. Synaptic Neurosci. 8, 20 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Nabavi, S. et al. Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc. Natl Acad. Sci. USA 110, 4027–4032 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Clayton, T. et al. A review of the updated pharmacophore for the α5 GABAA benzodiazepine receptor model. Int J. Med. Chem. 2015, 430248 (2015).

    PubMed  PubMed Central  Google Scholar 

  61. Navarro, J. F., Burón, E. & Martín-López, M. Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1389–1392 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Magnin, E. et al. Input-specific synaptic location and function of the α5 GABA. J. Neurosci. 39, 788–801 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Costello, E. J., Copeland, W. & Angold, A. Trends in psychopathology across the adolescent years: what changes when children become adolescents, and when adolescents become adults? J. Child Psychol. Psychiatry 52, 1015–1025 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Asher, M., Asnaani, A. & Aderka, I. M. Gender differences in social anxiety disorder: a review. Clin. Psychol. Rev. 56, 1–12 (2017).

    Article  PubMed  Google Scholar 

  65. Altemus, M., Sarvaiya, N. & Neill Epperson, C. Sex differences in anxiety and depression clinical perspectives. Front. Neuroendocrinol. 35, 320–330 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Eichenbaum, H. Prefrontal–hippocampal interactions in episodic memory. Nat. Rev. Neurosci. 18, 547–558 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Schwabe, M. R., Taxier, L. R. & Frick, K. M. It takes a neural village: circuit-based approaches for estrogenic regulation of episodic memory. Front. Neuroendocrinol. 59, 100860 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tuscher, J. J., Taxier, L. R., Schalk, J. C., Haertel, J. M. & Frick, K. M. Chemogenetic suppression of medial prefrontal-dorsal hippocampal interactions prevents estrogenic enhancement of memory consolidation in female mice. eNeuro 6, ENEURO.0451-18.2019 (2019).

  69. Caligioni, C. S. Assessing reproductive status/stages in mice. Curr. Protoc. Neurosci. 48, A.4I.1–A.4I.8 (2009).

  70. Cora, M. C., Kooistra, L. & Travlos, G. Vaginal cytology of the laboratory rat and mouse: review and criteria for the staging of the estrous cycle using stained vaginal smears. Toxicol. Pathol. 43, 776–793 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Seese, R. R., Wang, K., Yao, Y. Q., Lynch, G. & Gall, C. M. Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice. Proc. Natl Acad. Sci. USA 111, 16907–16912 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cox, B. M. et al. Acquisition of temporal order requires an intact CA3 commissural/associational (C/A) feedback system in mice. Commun. Biol. 2, 251 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Babayan, A. H. et al. Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J. Neurosci. 32, 12854–12861 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank E. Tran and G. Zalaya for assistance with behavioral studies. A.A.L. was supported by National Institute of Mental Health training grant T32-MH119049-02. J.C.L., Y.J., W.W., C.M.G. and G.L. were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant HD-089491, and G.L. was supported by National Science Foundation grant BCS-1941216. J.C.L., C.M.G. and G.L. were supported by National Institute on Drug Abuse grant DA-044118. G.L. and C.D.C. were supported by Office of Naval Research grant N00014182114, and C.D.C. was also supported by National Institutues of Health grant T32 AG00096-34.

Author information

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA

    Aliza A. Le, Julie C. Lauterborn, Yousheng Jia, Weisheng Wang, Conor D. Cox, Christine M. Gall & Gary Lynch

  2. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA

    Christine M. Gall

  3. Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA

    Gary Lynch

Authors
  1. Aliza A. Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie C. Lauterborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yousheng Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weisheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Conor D. Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christine M. Gall
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gary Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.A.L., C.M.G., G.L. and J.C.L. wrote the manuscript and designed experiments. A.A.L., J.C.L., Y.J. and W.W. performed experiments. C.D.C. constructed computerized analyses for the imaging and electrophysiological experiments.

Corresponding authors

Correspondence to Christine M. Gall or Gary Lynch.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Neuroscience thanks Paul Frankland, Natalie Tronson, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Sampling times for each cue in Object Location Memory (OLM), ‘Where’, and ‘What’ tasks across age and sex.

(a) OLM (5-min training session, tested 24 hours later): Sampling times of displaced (Novel) vs the stationary (Familiar) objects were compared for male and female mice of prepubescent (Prepub) and adult ages. Prepubescent females and adult males preferentially sampled the displaced object (***P = 0.0001, ***P = 0.0006, respectively; 2-tailed paired t-test), whereas non-proestrus adult females and prepubescent males did not (n.s. P = 0.21, P = 0.73, respectively; N = 7-18/group). (b) OLM (5- or 10-min training, tested 24-hours later): Adult females trained for 5 minutes during proestrus stage preferentially sampled the displaced object over the stationary object (**P = 0.004). Non-proestrus adult females and prepubescent males were trained for 10 minutes. Non-proestrus females preferred the displaced object (**P = 0.01), but the prepubescent males did not (n.s. P = 0.46; N = 6-9/group). (c) OLM (5-min training, 15-min delay): Adult females did not spend more time with the moved object (P = 0.99), whereas Prepub males preferred the moved object (***P = 0.0002; N = 8/group). (d) Left. Schematic for episodic ‘Where’ task with four odors (see Methods). Right. Sampling times of odors A-D for each group during the 5-minute training trial (One-way ANOVA: P > 0.05 within all age groups). (e) Sampling times for the ‘switched’ pair (Novel) vs the stationary pair. Prepubescent females and adult males sampled the ‘switched’ pair more than the stationary pair (2-tailed paired t-test: Prepub female **P = 0.008, Adult male ****P = 0.00004). Prepubescent male and adult females showed no preference (P = 0.65, P = 0.97, respectfully; N = 8-11). (f) Left. Schematic of the ‘What’ task (see Methods). Right. Sampling times for each odor (One-way ANOVA: P > 0.05 within all age groups; N = 8-9/group). (g) Sampling times for novel odor vs mean of the three familiar odors (2-tailed paired t-test: ***P < 0.001, **P < 0.01; N = 8-9/group). Data are represented as mean ± SEM. Detailed statistics are found in Supplementary Table 1.

Source data

Extended Data Fig. 2 Exploration data for 24-hour delay Object Location Memory in adult, non-proestrus female mice given L655,708.

(a) Sampling times for displaced (Novel) vs stationary (Familiar) object for Vehicle (2-tailed paired t-test: n.s. P = 0.85) and L655,708 (**P = 0.009). (b) Total sampling times for training and testing were comparable for treated vs. vehicle groups (2-tailed unpaired t-test: n.s. training P = 0.95, testing P = 0.98). (c) Distance traveled was comparable (2-tailed unpaired t-test: training P = 0.29, testing P = 0.71) and (d) velocity was similar between treatments (training P = 0.30, testing P = 0.73). For all panels, Vehicle N = 8, L655,708 N = 7. Data presented as mean ± SEM. Further statistics found in Supplementary Table 1.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2

Reporting Summary

Supplementary Table

Summary table for all statistical analysis

Supplementary Data

Source data for Supplementary Fig. 1

Supplementary Data

Source data for Supplementary Fig. 2

Source data

Source Data Fig. 1

Statistical Source Data for Fig. 1

Source Data Fig. 2

Statistical Source Data for Fig. 2

Source Data Fig. 3

Statistical Source Data for Fig. 3

Source Data Fig. 4

Statistical Source Data for Fig. 4

Source Data Fig. 5

Statistical Source Data for Fig. 5

Source Data Fig. 6

Statistical Source Data for Fig. 6

Source Data Extended Data Fig. 1

Statistical Source Data for Extended Data Fig. 1

Source Data Extended Data Fig. 2

Statistical Source Data for Extended Data Fig. 2

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Le, A.A., Lauterborn, J.C., Jia, Y. et al. Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases. Nat Neurosci 25, 180–190 (2022). https://doi.org/10.1038/s41593-021-01001-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-021-01001-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing