Synaptic Plasticity and Cognitive Enhancement: Bridging Neuropathological Cognitive Disorders to Emerging Neuropharmacological Strategies

Abstract

Synaptic plasticity refers to the fundamental process through which synaptic connections become stronger or weaker in response to experience, thereby forming the basis of learning and memory. Disruption of this process is increasingly regarded as a common underlying mechanism of several cognitive and neuropsychiatric disorders, including Alzheimer’s disease, major depressive disorder, schizophrenia, and cognitive aging. This review focuses on synaptic plasticity as a unifying framework that connects neuropathological cognitive disorders to emerging neuropharmacological strategies, with particular attention to clinical translation and precision medicine approaches. The review has three interrelated aims: (i) to clarify the molecular mechanisms that regulate synaptic plasticity, (ii) to investigate how these mechanisms become dysregulated in cognitive disorders, and (iii) to evaluate emerging pharmacological strategies targeting synaptic plasticity for cognitive enhancement. Among the areas receiving special attention are glutamatergic and GABAergic neurotransmission, neurotrophic signaling pathways such as brain-derived neurotrophic factor (BDNF), intracellular cascades including mechanistic target of rapamycin (mTOR) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), and epigenetic regulators. With respect to their effects on long-term potentiation, synaptogenesis, and neural circuit function, novel therapeutic agents, including ampakines, N-methyl-D-aspartate (NMDA) receptor modulators, and allosteric gamma-aminobutyric acid (GABA) receptor modulators, are also assessed in this review. In both healthy individuals and disease populations, the review further considers the cognitive and neuroplastic effects of nootropics, psychedelics, and other neuromodulatory compounds. As key enablers of translational progress, the review highlights recent advances in brain-penetrant and target-selective agents, as well as improvements in drug delivery systems and biomarker development. This review aims to provide a comprehensive framework for developing safer, more effective, and more precise interventions for cognitive impairment by integrating neurobiological mechanisms, neuropathological insights, and therapeutic innovation.