Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer-commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERβ or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERβ. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories. There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.
Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.
Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild type mice. Two factors contributed to this defect: i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and ii) impaired retrograde synaptic signaling by the endocannabinoid 2-archadonolglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB1, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.
Estradiol (E2) perfusion rapidly increases the strength of fast excitatory transmission and facilitates long-term potentiation in the hippocampus, two effects likely related to its memory-enhancing properties. Past studies showed that E2's facilitation of transmission involves activation of RhoA signaling leading to actin polymerization in dendritic spines. Here we report that brief exposure of adult male hippocampal slices to 1 nM E2 increases the percentage of postsynaptic densities associated with high levels of immunoreactivity for activated forms of the BDNF receptor TrkB and β1-integrins, two synaptic receptors that engage actin regulatory RhoA signaling. The effects of E2 on baseline synaptic responses were unaffected by pretreatment with the TrkB-Fc scavenger for extracellular BDNF or TrkB antagonism, but were eliminated by neutralizing antisera for β1-integrins. E2 effects on synaptic responses were also absent in conditional β1-integrin knockouts, and with inhibition of matrix metalloproteinases, extracellular enzymes that generate integrin ligands. We propose that E2, acting through estrogen receptor-β, transactivates synaptic TrkB and β1-integrin, and via mechanisms dependent on integrin activation and signaling, reversibly reorganizes the spine cytoskeleton and thereby enhances synaptic responses in adult hippocampus.
Positive allosteric modulators of AMPA-type glutamate receptors (ampakines) have been shown to rescue synaptic plasticity and reduce neuropathology in rodent models of cognitive disorders. Here we tested whether chronic ampakine treatment offsets age-related dendritic retraction in middle-aged (MA) rats. Starting at 10 months of age, rats were housed in an enriched environment and given daily treatment with a short half-life ampakine or vehicle for 3 months. Dendritic branching and spine measures were collected from 3D reconstructions of Lucifer yellow-filled CA1 pyramidal cells. There was a substantial loss of secondary branches, relative to enriched 2.5-month-old rats, in apical and basal dendritic fields of vehicle-treated, but not ampakine-treated, 13-month-old rats. Baseline synaptic responses in CA1 were only subtly different between the two MA groups, but long-term potentiation was greater in ampakine-treated rats. Unsupervised learning of a complex environment was used to assess treatment effects on behavior. Vehicle-and drug-treated rats behaved similarly during a first 30 min session in the novel environment but differed markedly on subsequent measures of long-term memory. Markov sequence analysis uncovered a clear increase in the predictability of serial movements between behavioral sessions 2 and 3 in the ampakine, but not vehicle, group. These results show that a surprising degree of dendritic retraction occurs by middle age and that this can be mostly offset by pharmacological treatments without evidence for unwanted side effects. The functional consequences of rescue were prominent with regard to memory but also extended to self-organization of behavior.
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