Silent Synapses in Multiple Sclerosis: From Synaptic Dysfunction to Reactivation‐Based Therapies—A Narrative Review of Cognitive and Neuroplasticity Outcomes

Silent synapses in multiple sclerosis (MS) represent a key yet underexplored concept in the pathology of this disease, playing a crucial role in cognitive impairments and reduced neuroplasticity. These synapses, due to the inactivity of AMPA receptors under pathological conditions, are unable to efficiently transmit neural signals, leading to disrupted neural communication. This dysfunction is particularly influenced by chronic inflammation, alterations in neurotransmitter dynamics, and a reduction in neurotrophic factors in MS patients. One of the key aspects of understanding silent synapses is that they not only have the potential for reactivation, but they can also contribute to the restoration of neural networks by re-establishing neuroplasticity. Recent research has shown that targeted treatments, including activating NMDA receptors, increasing brain-derived neurotrophic factor (BDNF), and using drugs like ketamine, help restore patients' cognitive function. Apart from pharmacological therapies, non-pharmacological strategies also include cognitive rehabilitation, physical activity, and noninvasive brain stimulation, which might promote synaptic plasticity and consequently quality of life. Therefore, reactivating latent synapses as a novel and interesting therapy strategy could not only improve cognitive performance in MS patients but also open the road for fresh methods to mend the nervous system and increase their quality of life. Though its specific form has not yet been thoroughly investigated, this approach offers great promise to become a viable MS treatment.