Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze

Dong, Zhifang; Bai, Yanrui; Wu, Xiaoge; Li, Hongjie; Gong, Bo; Howland, John G.; Huang, Yan; He, Wenting; Li, Tingyu; Wang, Yu Tian

doi:10.1016/j.neuropharm.2012.06.027

Cited by 190 publications

(151 citation statements)

References 52 publications

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“…First, our data suggest a conversion of some mature contacts to immature or silent type synapses, promoting circuit rewiring that facilitates learning by providing increased synaptic sites for information storage. As a consequence, the rapid effects of estrogens via ERα may cause weakening of some previously established memories (28) and facilitate their overwriting or updating if activated by a stimulus or a learning event (29). Second, the decrease in AMPA responses we observe can lead to an increase in the signal-to-noise ratio that improves learning and memory.…”

Section: Discussionmentioning

confidence: 78%

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements

Phan

Suschkov

Molinaro

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

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Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.immature synapse | short-term memory | structural plasticity | synaptic plasticity | signal-to-noise ratio E stradiol rapidly and dramatically increases hippocampal dendritic spine and synapse density within minutes of application (1-4). There is a strong correlative association between estrogeninduced spinogenesis and improvements in cognition (5); however, the relationship of these structural changes to estrogen-induced alterations in hippocampal function is unclear. Our laboratory recently reported that the density of hippocampal CA1 pyramidal dendritic spines increases very rapidly after systemic treatment with 17β-estradiol or estrogen receptor (ER) -selective agonists in ovariectomized female mice, changes that are paralleled by learning enhancements (2, 3). Estrogen-induced rapid structural changes are substantial, increasing spine density by 30-50% within 15-40 min of hormone application (1-3, 6). As a result, adult rodents can experience the addition of thousands of CA1 synapses within a span of minutes after exposure to estradiol. These effects of estrogens reproduce the changes occurring during the 4-d estrous cycle of female rodents, which include the induction of CA1 spines (7).How these processes contribute to the behavioral changes observed after estradiol treatment is not understood. Estradiol enhances excitatory neurotransmission throughout the hippocampus (8-10), and activates BDNF signaling in the mossy fiber system (11). Dendritic spines turn over more rapidly in the hippocampus than in the neocortex (12), particularly in the case of estradiol-induced spines (13). Such rapid, transient, and apparently indiscriminate increases in excitatory synapse formation would seem, at first sight, to be more likely to interfere with preexisting brain circuits and impair normal information processing than to enhance cognitive function.How then, does enhancement of spine formation lead to improved ...

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Section: Discussionmentioning

confidence: 78%

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements

Phan

Suschkov

Molinaro

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

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“…Although pharmacological or genetic disruption of NMDAR-dependent LTD in the CA1 region is related to impairments in behavioral flexibility (23)(24)(25), the mechanism underlying the role of NMDAR-dependent synaptic plasticity in social recognition is not fully understood. Here we used Prex1 −/− mice and found a tight link between NMDAR-dependent LTD in the CA1 region and behavioral phenotypes including social recognition, reversal learning of spatial memory, and extinction training of contextual fear memory but found no correlation with repetitive grooming or with the delayed nonmatch to place T-maze task.…”

Section: Discussionmentioning

confidence: 99%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphatedependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateralcornus ammonis region 1 (SC-CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition defici...

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“…In addition, a high dose of corticotropin-releasing factor (CRF) injected into the locus coeruleus facilitates reversal learning in rats [27]. Stress-induced changes in neurotransmitters such as glutamate, dopamine, and serotonin may also play a role in reversal learning facilitation [14,15,28]. Future research integrating these and other mechanisms that cause the facilitation of late reversal learning following stress will increase the understanding of the diverse stress effects of stress on behavioral flexibility.…”

Section: Discussionmentioning

confidence: 99%

“…However, the influence of acute stress on forms of cognition dependent on prefrontal cortex (PFC) is less well defined [1]. Research regarding the influence of acute stress on PFC-dependent executive processing and cognitive/behavioral flexibility have been inconsistent, with some studies showing impaired performance [6][7][8][9] while others show facilitated performance [10][11][12][13][14], depending on the specific task and stressor.…”

Section: Introductionmentioning

confidence: 99%

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

Bryce

Howland

2015

Behavioural Brain Research

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The stress response is essential to the survival of all species as it maintains internal equilibrium and allows organisms to respond to threats in the environment. Most stress research has focused on the detrimental impacts of stress on cognition and behavior. Reversal learning, which requires a change in response strategy based on one dimension of the stimuli, is one type of behavioral flexibility that is facilitated following some brief stress procedures. The current study investigated a potential mechanism underlying this facilitation by blocking glucocorticoid receptors (GRs) during stress. Thirty-seven male Long Evans rats learned to discriminate between two images on a touchscreen, one of which was rewarded. Once a criterion was reached, rats received stress (30 min of restraint stress or no stress) and drug (GR antagonist RU38486 or vehicle) administration prior to each of the first 3 days of reversal learning. We expected that stress would facilitate reversal learning and RU38486 (10 mg/kg) would prevent this facilitation in both early (<50% correct in one session) and late (>50% correct in one session) stages of reversal learning. Results showed that stressed rats performed better than unstressed rats (fewer days for late reversal, fewer correction trials, and fewer errors) in the late but not early stage of reversal learning. RU38486 did not block the facilitation of RL by stress, although it dramatically increased response, but not reward, latencies. These results confirm the facilitation of late reversal by stress in a touchscreenbased operant task in rats and further our understanding of how stress affects higher level cognitive functioning and behavior.

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Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze

Cited by 190 publications

References 52 publications

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

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