Amelie Eichler

Heart failure is frequently accompanied by cognitive impairment, yet structural correlates in the brain remain incompletely defined. Here, we assessed whether chronic heart failure is associated with synaptic ultrastructural remodeling in the murine neocortex using a mouse model of arrhythmogenic cardiomyopathy caused by a point mutation in desmoglein-2 (Dsg2-W2A). Brains from aged adult homozygous Dsg2-W2A mice and age-matched wildtype controls were processed for transmission electron microscopy, and excitatory synapses in layer I of the prefrontal cortex were quantitatively assessed, with comparative analyses in the somatosensory cortex. In the prefrontal cortex, presynaptic terminal area and synaptic vesicle number were reduced in mutant mice, whereas postsynaptic measures were not altered. The prevalence of mitochondria and the spine apparatus within synapses was comparable between genotypes, suggesting no major loss of synapse-associated organelles. Finally, synaptic parameters in the prefrontal cortex did not show a systematic dependence on distance to local blood vessels. Together, these findings indicate moderate region- and compartment-specific synaptic ultrastructural alterations associated with Dsg2 cardiomyopathy and chronic heart failure, with predominant effects on presynaptic terminals.

The amyloid precursor protein (APP) is a transmembrane protein widely expressed throughout the brain, where it plays critical roles in both physiological and pathological states. APP undergoes complex post-translational processing by various secretases, a process that can lead to amyloid plaque formation via its amyloidogenic pathway. Consequently, APP has been extensively studied in the context of Alzheimer's disease (AD). However, emerging evidence highlights its physiological functions and the diverse roles of its cleavage fragments. This review explores the dual role of APP and its fragments, focusing on their contributions to synaptic structure, function, and plasticity. We summarize the mechanisms by which APP and its fragments influence synaptic dynamics and plasticity in the hippocampal CA1 region. These insights underline the importance of APP beyond amyloidogenesis, emphasizing its role in fundamental neurobiological processes and potential implications for understanding early AD-related synaptic dysfunction.

The interplay between neuronal structure and function underpins the dynamic nature of neocortical networks. Despite extensive studies in animal models, our understanding of structure–function interrelations in the adult human brain remains incomplete. Recent methodological advances have facilitated the functional analysis of individual neurons within the human neocortex, providing a new understanding of fundamental brain processes. However, the factors contributing to patient-specific neuronal properties have not been thoroughly explored. In this observational study, we investigated the structural and functional variability of superficial pyramidal neurons in the adult human neocortex. Using whole-cell patch-clamp recordings and post hoc analyses of dendritic spine morphology in acute neocortical slice preparations from surgical resections of seven patients, we assessed age-related effects on excitatory neurotransmission, membrane properties and dendritic spine morphologies. These results specify age as an endogenous factor that might affect the structural and functional properties of superficial pyramidal neurons.

SUMMARY: The perforant path provides the main cortical excitatory input to the hippocampus. Due to its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, a characterization of synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells is still pending. Here, we have used organotypic entorhino-hippocampal tissue cultures, in which the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be studied using whole-cell patch clamp recordings. Using cultures of wildtype mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared and differences in short-term plasticity were revealed. Since the perforant path is severely affected in Alzheimer’s disease, we used cultures of APP-deficient mice to address the role of the amyloid-precursor protein (APP) at this synapse. APP-deficiency caused alterations in excitatory neurotransmission at medial perforant path synapses that were accompanied by transcriptomic and ultrastructural changes. Moreover, the deletion of pre- but not postsynaptic APP through the local injection of Cre-expressing AAVs in conditional APP ^flox/flox tissue cultures increased the efficacy of neurotransmission at perforant path synapses. Together, these data suggest a physiological role for presynaptic APP at medial perforant path synapses, which may be adversely affected under conditions of altered APP processing.

Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata—a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

Microglia—the resident immune cells of the central nervous system—sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from the microglia in organotypic brain tissue cultures, while no changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.

The vitamin A derivative all-trans retinoic acid (atRA) is a key mediator of synaptic plasticity. Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. However, it remains unclear how atRA mediates brain region-specific effects on synaptic transmission and plasticity. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult male C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata. In contrast to what has been reported in other brain regions, no major changes in synaptic transmission were observed in the ventral and dorsal hippocampus 6 hours after atRA administration. Likewise, no evidence for changes in the intrinsic properties of hippocampal dentate granule cells was obtained in the atRA-treated group. Moreover, hippocampal transcriptome analysis revealed no essential changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, i.e., for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic transmission. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, thus extending our previous results on the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

A defining feature of the brain is the ability of its synaptic contacts to adapt structurally and functionally in an experience-dependent manner. In the human cortex, however, direct experimental evidence for coordinated structural and functional synaptic adaptation is currently lacking. Here, we probed synaptic plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid (atRA), a putative treatment for neuropsychiatric disorders such as Alzheimer’s disease. Our experiments demonstrated that the excitatory synapses of superficial (layer 2/3) pyramidal neurons underwent coordinated structural and functional changes in the presence of atRA. These synaptic adaptations were accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and required mRNA translation. It was not observed in synaptopodin-deficient mice, which lack spine apparatus organelles. We conclude that atRA is a potent mediator of synaptic plasticity in the adult human cortex.

Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence has demonstrated that inflammatory cytokines affect the ability of neurons to express plasticity. It has been well-established that inflammation-associated alterations in synaptic plasticity contribute to the development of neuropsychiatric symptoms. Nevertheless, diagnostic approaches and interventional strategies to restore inflammatory deficits in synaptic plasticity are limited. Here, we review recent findings on inflammation-associated alterations in synaptic plasticity and the potential role of the blood–brain interface, i.e., the blood–brain barrier, in modulating synaptic plasticity. Based on recent findings indicating that brain stimulation promotes plasticity and modulates vascular function, we argue that clinically employed non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, could be used for monitoring and modulating inflammation-induced alterations in synaptic plasticity.

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [ C57BL6-Tg(TNFa-eGFP) ] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.