UC Irvine

Studies dating back to the late 19th century have described distinct sex-biased advantages in various facets of memory: men show superiority in spatial memory, whereas females excel in verbal memory and facial recognition. While it is tempting to relate such sex differences to cultural and societal factors, much of these observations have also been consistent across rodents and other mammals. Further investigations over the past three decades have linked steroids, like estradiol, with synaptic plasticity thereby providing a convenient explanation for sex differences in cognition and learning. Research described in this dissertation evaluated the cellular mechanisms underlying sex differences in synaptic plasticity in rodent hippocampus and how this affects the threshold for enduring synaptic plasticity and learning. The first set of studies, described in Chapter Two, demonstrated that adult female, but not male, rodents use local estrogen and estrogen receptor α (ERα) for the induction of hippocampal long-term potentiation (LTP) and encoding of spatial memory. This sexual dimorphism was accompanied by a somewhat higher threshold for both synaptic plasticity and spatial learning in females as compared to males. Evidence pointed towards estrogen and synaptic estrogen receptors as the primary elements thresholding LTP. Given that estrogen levels are low prior to puberty we reasoned that sex differences in plasticity and learning might be absent in prepubescent animals. There have been many studies of structural and neurochemical changes in hippocampus up to the fourth post-natal week, but relatively little was known about possible changes in synaptic function over ages of puberty (~weeks 4 to 8) in either sex. As described in Chapter Three we found robust sex differences prior to puberty but differences were reversed from before to after puberty. Thus, prior to puberty LTP is more robust in females than in males whereas the opposite is true after puberty. These studies also identified a mechanism underlying the puberty-related decrease in female LTP: there is a substantial increase in the feedforward IPSCs that shunt the depolarization produced by the theta bursts used to induce LTP. This inhibition is governed by the levels of α5-GABAA receptors and studies showed that increases in α5 levels and function account for the lower facility for LTP with maturation in females. Finally, Chapter Four describes processes which account for the reduction in LTP threshold with late maturation in males. Specifically, in distinction from females, we found males rely on previously uncharacterized metabotropic functions of the NMDA receptor. This reliance on the metabotropic NMDA receptor, as with females, is reflected in behavior and appears to reflect sex-specific specializations in different facets of episodic-like memory. Overall, work in this dissertation has identified sexually dimorphic LTP mechanisms, how they affect LTP threshold at critical stages in life (pre- and post-puberty), and, concurrently, how they contribute to sex-biased advantages in specific episodic memory components that describe the content, spatial location, and temporal context.