Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol

Abstract

The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol–parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/−) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF+/− mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.

Sex differences in brain‐derived neurotrophic factor signaling and functions

“…However, neurite formation in the presence of BDNF -/uteri was not affected by estrogen, indicating that estrogen alters the neuritogenic properties of the rodent uterus by regulating BDNF synthesis. Another study using BDNF 1/mice demonstrated that estradiol replacement improved performance in the Y-maze and novel-object-recognition tests in ovariectomized WT but not in BDNF 1/mice (Wu et al, 2015). Thus, the integrity of BDNF/TrkB signaling is essential to some estrogen-mediated neurological action, but how these two pathways interact with each other remains mysterious.…”

Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

“…The most striking observation from this study was impaired generation and regulation of high‐frequency oscillations in BDNF +/− mice – specifically reduced ERPs and evoked beta power following auditory stimuli, as well as reduced ongoing gamma power. The impaired ability to generate appropriate responses to brief auditory stimuli may underlie sensorimotor gating and cognitive deficits previously observed in these mice (Manning & van den Buuse, ; Wu et al ., ), because these behaviours may rely on such responses (Jones et al ., ). Further, given post‐mortem findings of reduced BDNF levels in the brains of patients with schizophrenia (Weickert et al ., ), these findings promote this mouse model as one which could be used to study the relationships between deficits in BDNF signalling and oscillatory abnormalities which are relevant to schizophrenia.…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…This may be due to sex-specific developmental expression profiles of these genes, or sex steroid hormone influences (Wong et al 2009;Hill 2012a;Hill et al 2012b;Hill et al 2013). Indeed, recent work from our laboratory demonstrate that M a n u s c r i p t 29 estradiol regulates the expression of parvalbumin positive interneurons during adolescence in the dorsal hippocampus and maintains spatial memory in WT but not BDNF heterozygous ovariectomized mice, suggesting a role for BDNF in mediating the cognitive enhancing effects of estradiol (Wu et al 2015). This study, showing recovery of a core molecular feature of schizophrenia (reduced PV) suggests that estradiol, or estrogen-based therapies could be utilized as adjunctive treatments for the cognitive impairments associated with schizophrenia.…”

“…Both drug-induced as well as genetic models of schizophrenia have shown a significant role for sex steroid hormones in modulating behaviours with relevance to schizophrenia, in particular estradiol seems to have a beneficial effect on drug-induced pre-pulse inhibition (Gogos et al 2012), drug-induced latent inhibition deficits (Arad et al 2010) and geneticinduced molecular phenotypes Wu et al 2015). However, very little has been done to assess the beneficial effects of estradiol in developmental models of schizophrenia.…”