Unravelling the Brain Resilience Following Stroke: From injury to rewiring of the brain through pathway activation, drug targets, and therapeutic interventions

 

 Since I know I blew all my cognitive resilience just surviving my stroke I'm rebuilding it with lots of social connections, mostly at bars where jazz or trivia is played. Alcohol seems to be involved, so don't listen to me, I'm not medically trained.

 A researcher asked me where my resilience came from a few years ago. I had no answer, but this probably explains it.

Your Mindset Shapes Your Life – For Better or Worse by Debbie Hampton

resilience (25 posts to September 2020) Lots in these posts which your competent? doctor should have informed you of but didn't because incompetence in not following research!

Unravelling the Brain Resilience Following Stroke: From injury to rewiring of the brain through pathway activation, drug targets, and therapeutic interventions

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https://doi.org/10.1016/j.arr.2025.102780

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Highlights

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  Post-stroke Glutamate excitotoxicity triggers numerous pathways, resulting in synapse loss.
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  Stroke leads to excessive synaptic pruning, causing loss of functional synapses and neural network efficiency.
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  Therapeutic targets enhancing the synaptic plasticity improve post-stroke functional impairment.

Abstract

Synaptic plasticity is a neuron's intrinsic ability to make new connections throughout life. The morphology and function of synapses are highly susceptible to any pathological condition. Ischemic stroke is a cerebrovascular event that affects various brain regions, resulting in the loss of neural networks. Stroke can alter both structural and functional plasticity of synapses, leading to long-term functional disability. Upon ischemic insult, numerous glutamate-mediated synaptic destruction pathways and glial-mediated phagocytic activity are triggered, resulting in excessive synapse loss, altering synaptic plasticity. The conventional stroke therapies to improve synaptic plasticity are still limited and ineffectual, leading to sub-optimal recovery in patients. Therefore, promoting synaptic plasticity to ameliorate sensory-motor function may be a promising strategy for long-term recovery in stroke patients. Here, we review the involvement of different molecular pathways of glutamate and glia-mediated synapse loss, current pharmacological targets, and the emerging novel approaches to improve synaptic plasticity and sensory-motor impairment post-stroke.

Introduction

As we delve into the complexities of the mammalian brain, synaptic plasticity has become an intriguing area of research in the field of neuroscience (Citri and Malenka, 2008). Synaptic plasticity is a neurophysiological phenomenon within each synapse governed by various molecular pathways, synaptic proteins, and glial cells to create a large neural network (Bitar et al., 2024, Stampanoni Bassi et al., 2019). (You don't explain anything about what in synaptic plasticity creates resilience. I can only assume you're spouting something with no knowledge.)It is the ability of pre-existing synapses to modulate the strength of their synaptic connections and the efficacy of synaptic transmission in response to any activity (Magee and Grienberger, 2020). Growing evidences indicate that synaptic plasticity plays a pivotal role in organising and reorganising the neuronal circuits in the early development of the central nervous system (CNS), thereby controlling human behaviour, memory, and emotions (Ho et al., 2011). Structural plasticity refers to the adaptive modification in the synaptic structure, such as spine number, shape, and density (Sadigh-Eteghad et al., 2018a). In contrast, functional plasticity is the brain's ability to modify and adapt the functional characteristics of neurons that include long-term potentiation (LTP) and long-term depression (LTD) (Peters et al., 2018).

Ischemic stroke is an acute cerebrovascular accident due to the blockage of blood vessels in the brain tissue (Datta et al., 2020). The current conventional therapies for ischemic stroke include intravenous thrombolytics, i.e. tissue plasminogen activator(tPA) and mechanical thrombectomy (Hurd et al., 2021). The past strategies to improve post-stroke synaptic plasticity are still limited and have not been explored much. Currently, some of the novel strategies are gaining more attention for their promising results in numerous preclinical and clinical settings to improve long-term functional impairments (Marín-Medina et al., 2024a, Su and Xu, 2020a). Synaptic loss is the key hallmark of various neurological disorders, including stroke (Wilson et al., 2023). Upon ischemic insult, multiple cellular stress pathways get triggered, including glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, blood-brain barrier (BBB) disruption, immune and complement activation, neuroinflammation, and apoptosis, which eventually causes synaptic loss (Tuo et al., 2022). Following stroke in human 32000 neurons, 230 million synapses, and 200 meters(218 yards) of myelinated fibres are lost each second which accelerates the aging by 8.7 h, and per stroke around 1.2 billion neurons, 8.3 trillion synapses, and 7140 km(4470 miles) of myelinated fibres are destroyed which accelerates the aging by 36 years (Saver, 2006). Various studies have reported that stroke can dysregulate both structural and functional synaptic plasticity, leading to post-stroke sensory-motor impairments (Yang et al., 2018, Wang et al., 2022a).

Synapse is the site of communication or the junction of neurons, enabling a well-organised flow of information throughout the brain (Caire et al., 2018). They are the highest energy-consuming sub-cellular compartment of the brain for performing all synaptic activity (Faria-Pereira and Morais, 2022, Fedorovich and Waseem, 2018). Mitochondria are mainly present on the synaptic terminal to meet the excessive energy demand for synaptic transmission through Adenosine triphosphate (ATP) production and Ca²⁺ buffering (Sheng and Cai, 2012, Duarte et al., 2023, Lee et al., 2018, Devine and Kittler, 2018). During ischemic injury, glutamate excitotoxicity alters mitochondrial functioning and trafficking by increasing the production of cofilin rods, thus, ATP supply to the synapses is interrupted. In addition, numerous other glutamate-mediated molecular pathways get triggered, resulting in altered synaptic plasticity and synapse loss (Shu et al., 2019a). Moreover, glial cells like microglia and astrocytes are well-known synaptic sculptors that play an important role in synaptic pruning and maintaining brain homeostasis (Huo et al., 2024, Bosworth and Allen, 2017). Synaptic pruning is part of the CNS development process, including the targeted elimination of non-functional synapses to maintain their appropriate number and improve neural network efficiency (Cornell et al., 2022). Nevertheless, microglia and astrocytes act as double-edged swords upon stroke, engulfing the viable synapses by recognising the “eat me” signals through their surface receptors, resulting in synaptic loss (Neher et al., 2013). Various proinflammatory cytokines are released during the glia-mediated synaptic loss, leading to disruption of the BBB, further aggravating brain injury and synaptic plasticity (Alsbrook et al., 2023).

This present review comprehensively describes the molecular basis of glutamate and glia-mediated synaptic loss in ischemic stroke, current pharmacological targets (Table 1), and the emerging novel approaches for enhancing synaptic plasticity to overcome sensory-motor disability post-stroke. A diversified literature search was conducted in the PubMed, Google Scholar, ScienceDirect, and ResearchGate databases over the last 25 years. Relevant studies were found by using keywords like (synaptic plasticity, stroke, synaptic pruning, stem cell, neurostimulation, optogenetics). Exclusion criteria involve studies irrelevant to the topic and those published in languages other than English.

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