Roles of α- and β-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle

Establishing clear effects of gender and natural hormonal changes during female ovarian cycles on cognitive function has often proved difficult. Here we have investigated such effects on the formation and long-term (24 h) maintenance of social recognition memory in mice together with the respective involvement of α- and β-estrogen receptors using α- and β-estrogen receptor knockout mice and wildtype controls. Results in wildtype animals showed that while females successfully formed a memory in the context of a habituation/dishabituation paradigm at all stages of their ovarian cycle, only when learning occurred during proestrus (when estrogen levels are highest) was it retained after 24 h. In α-receptor knockout mice (which showed no ovarian cycles) both formation and maintenance of this social recognition memory were impaired, whereas β-receptor knockouts showed no significant deficits and exhibited the same proestrus-dependent retention of memory at 24 h. To investigate possible sex differences, male α- and β-estrogen receptor knockout mice were also tested and showed similar effects to females excepting that α-receptor knockouts had normal memory formation and only exhibited a 24 h retention deficit. This indicates a greater dependence in females on α-receptor expression for memory formation in this task. Since non-specific motivational and attentional aspects of the task were unaffected, our findings suggest a general α-receptor dependent facilitation of memory formation by estrogen as well as an enhanced long-term retention during proestrus. Results are discussed in terms of the differential roles of the two estrogen receptors, the neural substrates involved and putative interactions with oxytocin.     

Transport of animals between rooms: a little-noted aspect of laboratory procedure that may interfere with memory

This study investigated the effects of transporting animals from the experimental room to the animal facility in between experimental sessions, a procedure routinely employed in experimental research, on long-term social recognition memory. By using the intruder-resident paradigm, independent groups of Wistar rats exposed to a 2-h encounter with an adult intruder were transported from the experimental room to the animal facility either 0.5 or 6 h after the encounter. The following day, residents were exposed to a second encounter with either the same or a different (unfamiliar) intruder. Resident's social and non-social behaviors were carefully scored and subjected to Principal Component Analysis, thus allowing to parcel out variance and relatedness among these behaviors. Resident rats transported 6 h after the first encounter exhibited reduced amount of social investigation towards familiar intruders, but an increase of social investigation when exposed to a different intruder as compared to the first encounter. These effects revealed a consistent long-lasting (24 h) social recognition memory in rats. In contrast, resident rats transported 0.5 h after the first encounter did not exhibit social recognition memory. These results indicate that this common, little-noted, laboratory procedure disturbs long-term social recognition memory.     

Neuroendocrine basis of social recognition

Studies conducted in the past two years have yielded several new insights about neuroendocrine regulation of social recognition. The social recognition deficits seen in oxytocin knockout mice have now been demonstrated in both males and females, as well as in female estrogen receptor knockout mice. The male vasopressin V1A receptor knockout mouse (but not V1B) has a profound social recognition deficit. Preliminary evidence suggests that female V1B receptor knockout mice could also have social memory deficits. Several lines of evidence have emerged that indicate that neuropeptide regulation is significantly modulated by gonadal and corticosteroid activation.     

Dihydrotestosterone modulates spatial working-memory performance in male mice

Androgens affect cognitive processes in both humans and animals. The effects of androgens may be limited to certain cognitive domains, specifically spatial memory, but this hypothesis remains elusive. Here, we tested castrated and sham-operated mice in various behavioral tasks to ask whether androgens affect multiple or specific cognitive domains in male mice. Castration impaired spatial working memory performance in the delayed matching to place water maze task following a 1-h, but not a 1-min, retention interval, as has been reported for rats. In contrast, castration had no effect on novel object recognition memory, spatial reference memory in the water maze, motor coordination, or passive avoidance memory. Castration increased anxiety-like behavior in the open field test, but not the elevated zero maze. Finally, we assessed the effects of androgen replacement with non-aromatizable dihydrotestosterone on spatial working memory following various retention intervals. Dihydrotestosterone recovered spatial memory performance following a 24-h, but not a 1-h retention interval, and had no effect at other retention intervals. These data support that in male mice androgens specifically affect spatial working memory performance, and that the neurobiological processes underlying spatial memory formation may be differentially affected by androgens.     

genetic overexpression of NR2B subunit enhances social recognition memory for different strains and species

The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2B:NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species.     

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.     

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2 h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2 weeks improved prenatal VPA-induced social interaction deficits for at least 24 h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.     

Estrogen involvement in social behavior in rodents: Rapid and long-term actions

This article is part of a Special Issue (“Estradiol and cognition”).Estrogens have repeatedly been shown to influence a wide array of social behaviors, which in rodents are predominantly olfactory-mediated. Estrogens are involved in social behavior at multiple levels of processing, from the detection and integration of socially relevant olfactory information to more complex social behaviors, including social preferences, aggression and dominance, and learning and memory for social stimuli (e.g. social recognition and social learning). Three estrogen receptors (ERs), ERα, ERβ, and the G protein-coupled ER 1 (GPER1), differently affect these behaviors. Social recognition, territorial aggression, and sexual preferences and mate choice, all requiring the integration of socially related olfactory information, seem to primarily involve ERα, with ERβ playing a lesser, modulatory role. In contrast, social learning consistently responds differently to estrogen manipulations than other social behaviors. This suggests differential ER involvement in brain regions important for specific social behaviors, such as the ventromedial and medial preoptic nuclei of the hypothalamus in social preferences and aggression, the medial amygdala and hippocampus in social recognition, and the prefrontal cortex and hippocampus in social learning. While the long-term effects of ERα and ERβ on social behavior have been extensively investigated, our knowledge of the rapid, non-genomic, effects of estrogens is more limited and suggests that they may mediate some social behaviors (e.g. social learning) differently from long-term effects. Further research is required to compare ER involvement in regulating social behavior in male and female animals, and to further elucidate the roles of the more recently described G protein-coupled ERs, both the GPER1 and the Gq-mER.     

Involvement of estrogen receptor alpha, beta and oxytocin in social discrimination: A detailed behavioral analysis with knockout female mice

Social recognition, processing, and retaining information about conspecific individuals is crucial for the development of normal social relationships. The neuropeptide oxytocin (OT) is necessary for social recognition in male and female mice, with its effects being modulated by estrogens in females. In previous studies, mice whose genes for the estrogen receptor-alpha (alpha-ERKO) and estrogen receptor-beta (beta-ERKO) as well as OTKO were knocked out failed to habituate to a repeatedly presented conspecific and to dishabituate when the familiar mouse is replaced by a novel animal (Choleris et al. 2003, Proc Natl Acad Sci USA 100, 6192-6197). However, a binary social discrimination assay, where animals are given a simultaneous choice between a familiar and a previously unknown individual, offers a more direct test of social recognition. Here, we used alpha-ERKO, beta-ERKO, and OTKO female mice in the binary social discrimination paradigm. Differently from their wild-type controls, when given a choice, the KO mice showed either reduced (beta-ERKO) or completely impaired (OTKO and alpha-ERKO) social discrimination. Detailed behavioral analyses indicate that all of the KO mice have reduced anxiety-related stretched approaches to the social stimulus with no overall impairment in horizontal and vertical activity, non-social investigation, and various other behaviors such as, self-grooming, digging, and inactivity. Therefore, the OT, ER-alpha, and ER-beta genes are necessary, to different degrees, for social discrimination and, thus, for the modulation of social behavior (e.g. aggression, affiliation).     

Long-lasting consequences of neonatal maternal separation on social behaviors in ovariectomized female mice

Maternal separation (MS) stress is known to induce long-lasting alterations in emotional and anxiety-related behaviors, but effects on social behaviors are not well defined. The present study examined MS effects on female social behaviors in the social investigation (SIT) and social preference (SPT) tests, in addition to non-social behaviors in the open-field (OFT) and light-dark transition (LDT) tests in C57BL/6J mice. All females were tested as ovariectomized to eliminate confounding effects of endogenous estrogen during behavioral testing. Daily MS (3 hr) from postnatal day 1 to 14 did not affect anxiety levels in LDT, but were elevated in OFT with modified behavioral responses to the novel environment. Furthermore, MS altered social investigative behaviors and preference patterns toward unfamiliar stimulus mice in SIT and short- and long-term SPT paradigms. In SIT, MS reduced social investigation duration and increased number of stretched approaches towards both female and male unfamiliar stimulus mice, suggesting increased social anxiety levels in MS females. Similarly, MS heightened levels of social anxiety during short-term SPT but no MS effect on social preference was found. On the other hand, MS females displayed a distinctive preference for female stimuli, unlike control females, when tested for long-term SPT over a prolonged period of 5 days. Evaluation of FosB expression in the paraventricular nucleus, medial and central amygdala following stimulus exposure demonstrated greater number of FosB immunopositive cells in all three brain regions in MS females compared to control females. These results suggest that MS females might differ in neuroendocrine responses toward unfamiliar female and male opponents, which may be associated with modifications in social behaviors found in the present study. Taken together, this study provides new evidence that early life stress modifies female social behaviors by highlighting alterations in behavioral responses to situations involving social as well as non-social novelty.     

Genetic loss of diazepam binding inhibitor in mice impairs social interest

Neuropsychiatric disorders in which reduced social interest is a common symptom, such as autism, depression, and anxiety, are frequently associated with genetic mutations affecting γ‐aminobutyric acid (GABA)ergic transmission. Benzodiazepine treatment, acting via GABA type‐A receptors, improves social interaction in male mouse models with autism‐like features. The protein diazepam binding inhibitor (DBI) can act as an endogenous benzodiazepine, but a role for DBI in social behavior has not been described. Here, we investigated the role of DBI in the social interest and recognition behavior of mice. The responses of DBI wild‐type and knockout male and female mice to ovariectomized female wild‐type mice (a neutral social stimulus) were evaluated in a habituation/dishabituation task. Both male and female knockout mice exhibited reduced social interest, and DBI knockout mice lacked the sex difference in social interest levels observed in wild‐type mice, in which males showed higher social interest levels than females. The ability to discriminate between familiar and novel stimulus mice (social recognition) was not impaired in DBI‐deficient mice of either sex. DBI knockouts could learn a rotarod motor task, and could discriminate between social and nonsocial odors. Both sexes of DBI knockout mice showed increased repetitive grooming behavior, but not in a manner that would account for the decrease in social investigation time. Genetic loss of DBI did not alter seminal vesicle weight, indicating that the social interest phenotype of males lacking DBI is not due to reduced circulating testosterone. Together, these studies show a novel role of DBI in driving social interest and motivation.     

Age-related deficits of long-term memory in the crab Chasmagnathus

Short and long-term memory in adult crabs Chasmagnathus granulatus of different age are evaluated in two learning paradigms: habituation to a visual danger stimulus and appetitive conditioning. No difference between young, middle-aged and aged animals is found in short-term habituation with 15 training trials. A good level of retention of the habituated response at 24 h is exhibited by young and middle-aged crabs but a poor one by aged crabs. When the training-to-testing interval is lengthened to 48 h or the training session reduced to 7 trials, young and middle-aged crabs continue to show long-term habituation but aged individuals exhibit no retention at all. As regards appetitive conditioning, young, middle-aged and aged crabs present similar short-term memory with 5 training trials and similar long-term memory when tested at 24 h, but an age-related deficit in long-term retention is exhibited when the intersession interval is lengthened to 48 h or the training reduced to 3 trials. Thus, a reduction of long-term memory related to age is demonstrated in the crab Chasmagnathus. Since it is shown in two different learning paradigms, the possibility of explaining the deficit in terms of a failure in memory mechanisms due to aging rather than as a consequence of ontogenetic shift in the crab's behavior is discussed.     

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration.     

(−)-Linalool, a naturally occurring monoterpene compound, impairs memory acquisition in the object recognition task, inhibitory avoidance test and habituation to a novel environment in rats

It is known that (−)-linalool is a competitive antagonist of NMDA receptors, which play a key role in the learning and memory processes; however, only a few studies have reported a possible interference of (−)-linalool in memory. The purpose of this study was to investigate the (−)-linalool effects on acquisition of short- and long-term memories through the objects recognition task, inhibitory avoidance test and habituation to a novel environment. Furthermore, the open field test was used to investigate the interference of (−)-linalool in motivation, locomotion and exploration by animals. Wistar male adult rats received an intraperitoneal injection (i.p.) of saline (NaCl 0.9%), tween 5% or (−)-linalool (50 or 100 mg/kg) before training in the tasks; MK-801 (0.1 mg/kg), a glutamate antagonist, was used as positive control. Short-term (STM) and long-term (LTM) memories were tested 1.5 and 24 h after training, respectively, in the inhibitory avoidance and recognition objects. The results suggested that (−)-linalool (as 50- and 100-mg/kg doses) impaired LTM acquisition, but not STM acquisition, in the object recognition task. In the inhibitory avoidance test, animals receiving linalool (both doses) showed impairment in acquisition of both memories measured. In the open field test, the animals that received (−)-linalool showed no significant difference in the crossings and latency to start the locomotion in any of the doses tested, although (−)-linalool 100 mg/kg reduced rearing behavior. When re-exposed to open field 24 h after training, the rats that received (−)-linalool 100 mg/kg showed no habituation. Taken together, these data suggested that (−)-linalool was able to impair the acquisition of memory in rats, which can be associated to (−)-linalool antagonist capacity as regards NMDA glutamatergic receptors, since other glutamate antagonists also seem to affect memory.     

Decades-long social memory in bottlenose dolphins

Long-term social memory is important, because it is an ecologically relevant test of cognitive capacity, it helps us understand which social relationships are remembered and it relates two seemingly disparate disciplines: cognition and sociality. For dolphins, long-term memory for conspecifics could help assess social threats as well as potential social or hunting alliances in a very fluid and complex fission–fusion social system, yet we have no idea how long dolphins can remember each other. Through a playback study conducted within a multi-institution dolphin breeding consortium (where animals are moved between different facilities), recognition of unfamiliar versus familiar signature whistles of former tank mates was assessed. This research shows that dolphins have the potential for lifelong memory for each other regardless of relatedness, sex or duration of association. This is, to my knowledge, the first study to show that social recognition can last for at least 20 years in a non-human species and the first large-scale study to address long-term memory in a cetacean. These results, paired with evidence from elephants and humans, provide suggestive evidence that sociality and cognition could be related, as a good memory is necessary in a fluid social system.     

Overexpression of the NR2A subunit in the forebrain impairs long‐term social recognition and non‐social olfactory memory

Animals must recognize and remember conspecifics and potential mates, and distinguish these animals from potential heterospecific competitors and predators. Despite its necessity, aged animals are known to exhibit impaired social recognition memory. As the brain ages, the ratio of NR2A:NR2B in the brain increases over time and has been postulated to underlie the cognitive decline observed during the aging process. Here, we test the hypothesis that an increased NR2A:NR2B subunit ratio underlies long‐term social recognition memory. Using transgenic overexpression of NR2A in the forebrain regions, we investigated the ability of these mice to learn and remember male and female conspecifics, mice of another strain and animals of another rodent species, the rat. Furthermore, due to the importance of olfaction in social recognition, we tested the olfactory memory in the NR2A transgenic mice. Our series of behavioral experiments revealed significant impairments in the NR2A transgenic mice in long‐term social memory of both male and female conspecifics. Additionally, the NR2A transgenic mice are unable to recognize mice of another strain or rats. The NR2A transgenic mice also exhibited long‐term memory impairments in the olfactory recognition task. Taken together, our results provide evidence that an increased NR2A:NR2B ratio in the forebrain leads to reduced long‐term memory function, including the ethologically important memories such as social recognition and olfactory memory .     

Effects of estradiol benzoate on learning-memory behavior and synaptic structure in ovariectomized mice

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by altering neuronal plasticity, including increased hippocampus CA1 dendritic spine density and enhanced long-term potentiation (LTP). In the present study, we investigated the effects of estrogen on the ultrastructural modifications in cerebral frontal cortex and hippocampus of female ovariectomized mice. One week after ovariectomy (Ovx), ICR female mice received daily injection of estradiol benzoate (EB, 20, 100, 200 microg/kg, s.c.) for 4-5 weeks. Spatial memory was then tested in the water maze, and the overall locomotor activity was monitored in open field. Synaptic morphologic parameters were examined using a graph analyzer. The results from open field did not show any alterations in locomotor activity following Ovx and EB replacement. Both the latency to find the platform and the distance to reach the platform were significantly reduced in Ovx mice by EB at 20 or 100 microg/kg when compared to vehicle treated Ovx mice. The results from synaptic ultrastructural measurement and analysis did not show any differences in hemispheric or hippocampal volumes, the numeric synaptic density, the length of active zones, or the curvature of synaptic interface among Sham, Ovx, and Ovx plus EB replacement mice. However, EB replacement effectively normalized the changes induced by Ovx, reducing the width of the synaptic cleft, enlarging the thickness of postsynaptic density (PSD), and increasing the number of synaptic vesicles in the presynapse in both cerebral cortex Fr1 and hippocampus CA1 areas. These results suggest that the beneficial effects of EB on improving memory behavior of Ovx female mice are associated with the changes of some subtle structural parameters of synapses, including the width of PSD and synaptic cleft rather than some basic and permanent structure in frontal cortex and hippocampus regions.     

Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus)

Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2 h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3 min exposure lasted for at least 24 h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48 h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20 min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli.     

Impaired social memories in 129P2 inbred mice are rescued by reduced Csk expression

The C-terminal Src kinase (Csk) is an essential signaling factor guiding central nervous system (CNS) development. In the adult brain, Csk-mediated control of Src may also modulate glutamatergic synaptic transmission and N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity. The regulation of N-methyl-d-aspartate (NMDA)-dependent plasticity by a myriad of kinase cascades has been investigated intensively during spatial and fear learning, while little is known about the regulatory kinases and role of NMDA-dependent plasticity during equally critical forms of social learning. We assessed social memory in Csk(+/+) and Csk(+/-) mice backcrossed onto 129P2, an inbred strain with wild-type impairments in social memory. Reduced Csk expression in Csk(+/-) mice was associated with increased NMDAR subunit 2B (NR2B) phosphorylation in the amygdala (AM) and olfactory bulb (OB), and with markedly improved social recognition memory and social transmission of food preference (STFP). In contrast, phosphorylation of NR2B was only slightly increased in the hippocampus of 129P2/Csk(+/-) mice, and the poor spatial object recognition memory of wild-type 129P2/Csk(+/+) mice was not rescued by reduced Csk expression. The Csk pathway appears to be a critical signaling cascade regulating social learning and memory, and presents a possible therapeutic target in diseases such as autism that are characterized by aberrant social behaviors.