Behavioural Brain Research 164 (2005) 128–131 Short communication Beta estrogen receptor knockout (BERKO) mice present attenuated hippocampal CA1 long-term potentiation and related memory deficits in contextual fear conditioning Mark Day * , Amy Sung, Sheree Logue, Mark Bowlby, Robert Arias WyethResearch,DiscoveryNeuroscience,CN8000,Princeton,NJ08543,USA Received 14 March 2005; received in revised form 4 May 2005; accepted 9 May 2005 Available online 27 July 2005 Abstract Estrogen has marked effects on hippocampal synaptic plasticity. We demonstrate that male and female 3-month-old beta estrogen receptor knockout (BERKO) mice show profound memory impairment in a hippocampus-mediated fear-conditioning paradigm. Subsequently, hip- pocampal slices prepared from behaviorally naive female BERKO mice were examined electrophysiologically. These were found to have robust synaptic deficits, compared to slices from age-matched wild type controls, both in terms of their input–output curves and their expres- sion of long-term-potentiation in area CA1. This report provides the first concrete evidence of significant hippocampal synaptic plasticity and memory deficits in the BERKO mouse. © 2005 Published by Elsevier B.V. 1. Introduction Two forms of the estrogen receptor have been identified, designated ER and ER. The predominant receptor sub- type in the rodent CNS is ER, although both subtypes are widely expressed [12,13,15,22]. In reproductive tissues, how- ever, there is little or no expression of ER, and so ER predominates there [5,14]. Not surprisingly, ER knockout mice (BERKO) mice have normal reproductive functioning whilst those functions are severely impaired in ERKO mice [10,11,18]. BERKO mice have also been reported to have spa- tial learning deficits in the Morris watermaze [9], profound neuronal loss and shrinkage by 3 months of age [23], cellular disorganisation, astroglial proliferation, increased apoE and significant amyloid plaque deposition throughout the CNS by 12 months of age. Recent neurochemical data also demon- strate that BERKO mice have depleted dopamine and sero- tonin levels in regions of the brain associated with learning and memory [6]. Moreover, these neurochemical depletions in BERKO mice are not reversed by endogenous or exoge- * Corresponding author. Tel.: +1 732 274 4740; fax: +1 732 274 4020. E-mailaddress: Daym1@wyeth.com (M. Day). nous estrogen. In contrast, no such defects have been reported in the brains of ERKO mice. The cognitive and neurodegenerative defects found in BERKO mice are intriguing given that the non-selective estrogen agonist 17-estradiol exerts profound positive effects on hippocampal dendritic morphology [19,20] and synaptic function [2], particularly since the mammalian hip- pocampus plays an important role in several distinct learning and memory processes [3,7]. Therefore, it is reasonable to expect that the deletion of ER, but not ER, would ren- der negative effects on hippocampal synaptic plasticity and information processing. To test this hypothesis, 20 female and 20 male BERKO mice and their wild type (WT) counterparts were trained in a fear-conditioning paradigm. Mice were trained (day 1) and tested (day 2) on two consecutive days. On day 1, animals were given 2min in an operant chamber, followed by a 30 s tone and a subsequent 2 s shock (0.7 mA). This trial was repeated once with an inter-trial-interval (ITI) of 2 min. On day 2, animals were placed back in the context to assess their memory of the context–shock relationship, a measure of hippocampal dependent learning. Whilst both male and female WT subjects remembered the context, as 0166-4328/$ – see front matter © 2005 Published by Elsevier B.V. doi:10.1016/j.bbr.2005.05.011