Journal of Alzheimers Disease & Parkinsonism
Open Access

Synaptic dysfunction refers to the disruption of normal synaptic communication between neurons in the brain and nervous system. Synapses are the junctions where neurons transmit signals to one another or to target cells such as muscles. This transmission is crucial for every aspect of brain function, including learning, memory, perception, and behavior. When synaptic function is impaired, the effects can range from subtle cognitive changes to severe neurological and psychiatric disorders. Synaptic dysfunction is increasingly recognized as a key early event in many neurodegenerative diseases, as well as in developmental and psychiatric conditions.

A typical synapse consists of a presynaptic neuron that releases neurotransmitters, a synaptic cleft, and a postsynaptic neuron with receptors that bind those neurotransmitters. Synaptic communication depends on a finely tuned balance of chemical and electrical signals. Neurotransmitters like glutamate, GABA, dopamine, serotonin, and acetylcholine must be released in the right amounts, at the right time, and received properly to maintain normal function. Disruption at any stage of this process neurotransmitter synthesis, release, receptor function, or signal termination can lead to synaptic dysfunction.

One major cause of synaptic dysfunction is the accumulation of toxic proteins associated with neurodegenerative diseases. In Alzheimer’s disease, soluble amyloid-beta oligomers interfere with synaptic plasticity and block Long-Term Potentiation (LTP), which is essential for memory formation. These oligomers bind to synaptic receptors and disrupt calcium signaling, leading to synapse loss before widespread neuron death occurs. Similarly, in Parkinson’s disease, misfolded alpha- synuclein can accumulate at synapses, impairing neurotransmitter release and vesicle recycling. Tau protein, when hyperphosphorylated in Alzheimer’s and related disorders, can also disrupt the transport of synaptic components along axons, leading to synaptic failure.

Genetic mutations can also contribute to synaptic dysfunction. In Autism Spectrum Disorders (ASD), mutations in genes which are critical for synapse formation and function, have been identified. These mutations can alter synaptic architecture and disrupt the balance between excitatory and inhibitory signaling, leading to impaired social communication and repetitive behaviors. In schizophrenia, abnormalities in glutamatergic and dopaminergic synapses have been observed, contributing to cognitive and perceptual disturbances.

Synaptic dysfunction is not only a feature of chronic diseases but also plays a role in acute conditions. For instance, in epilepsy, abnormal synaptic transmission can lead to excessive neuronal firing and seizures. In stroke or traumatic brain injury, the sudden loss of blood flow or physical damage disrupts synaptic connectivity, impairing neural circuits and cognitive functions.

Mitochondrial dysfunction and oxidative stress also affect synaptic health. Synapses have high energy demands, and when mitochondria fail to meet those demands, neurotransmission falters. Reactive oxygen species can damage synaptic proteins and lipids, further impairing communication. Inflammation, particularly chronic neuroinflammation mediated by activated microglia and astrocytes, can also lead to synaptic pruning or loss, especially in diseases like Alzheimer’s and multiple sclerosis. Detecting and studying synaptic dysfunction has been advanced by modern tools such as electrophysiology, high-resolution imaging, and molecular profiling.

Synaptic dysfunction is a central mechanism underlying many neurological and psychiatric diseases. It often precedes and contributes to neuronal death, making it a critical target for early diagnosis and intervention. As our understanding of synaptic biology deepens, so too does the potential for developing precise and effective therapies aimed at preserving and restoring brain function. In depression, selective Serotonin Reuptake Inhibitors (SSRIs) enhance synaptic serotonin levels. Experimental treatments, including synapse-protective agents, neurotrophic factors, and targeted gene therapies, are being studied to reverse or slow synaptic damage in various disorders.