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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

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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.

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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.

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.

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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.

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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

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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.

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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.

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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

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