Synapsin is a family of proteins that acts as a central regulator of communication between neurons in the central nervous system. It is one of the most abundant proteins found inside the presynaptic terminal, the specialized ending of a neuron that sends signals. Synapsin’s primary function is to govern the availability of chemical messengers, known as neurotransmitters, directly influencing the strength and speed of brain signaling.
Synapsin: Molecular Identity and Location
Synapsin is a family of related phosphoproteins encoded by three distinct genes: Synapsin I, Synapsin II, and Synapsin III. These genes produce at least nine different protein isoforms through alternative splicing. Synapsins are neuron-specific phosphoproteins, making up approximately 6% of the total protein mass in synaptic vesicles.
All Synapsin types are primarily located in the presynaptic terminal of the neuron. They are associated with the cytosolic side of synaptic vesicles, the small, membrane-bound sacs that store neurotransmitters. Synapsins I and II are widely expressed in the mature nervous system, regulating neurotransmitter release.
Synapsin III is more prominent during early neuronal development, and its expression is less confined to synaptic terminals in the adult brain. While all Synapsins share a highly conserved N-terminal region, their C-terminal regions vary. These structural differences contribute to their distinct, though overlapping, roles in the timing and location of neurotransmitter release.
The Core Mechanism of Neurotransmitter Release
Synapsin acts as a tether, anchoring synaptic vesicles within the presynaptic terminal. By interacting with the actin cytoskeleton, Synapsin keeps a large pool of vesicles clustered together. This clustered population is known as the “reserve pool,” as these vesicles are held away from the active zone, the specific site where release occurs.
This tethering prevents the premature release of neurotransmitters, ensuring the neuron only fires when signaled. The reserve pool supplies the active zone with fresh vesicles during intense or prolonged neuronal activity. Without this reservoir, synapses would quickly run out of messengers, leading to synaptic fatigue.
When an electrical signal (an action potential) arrives at the presynaptic terminal, a precise molecular sequence must occur for release. The signal causes Synapsin to detach from the synaptic vesicle membrane and the cytoskeleton. This detachment is called vesicle mobilization, which frees the vesicle to move toward the active zone.
Once mobilized, the vesicle docks at the active zone, fuses with the presynaptic membrane, and releases its contents into the synaptic cleft. Synapsin controls the supply chain of synaptic vesicles, regulating the synapse’s ability to sustain signaling, especially under high-demand conditions.
Control Switch: Regulation by Phosphorylation
Synapsin’s tethering action is controlled by phosphorylation, a chemical modification process. This involves the attachment of a phosphate group to specific amino acid residues on the Synapsin protein. Phosphorylation is a rapid, reversible mechanism that allows the neuron to instantly respond to incoming activity.
The electrical signal arriving at the terminal triggers an influx of calcium ions, which activates several protein kinases, the enzymes responsible for adding the phosphate groups. Key kinases involved include Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) and Protein Kinase A (PKA).
The addition of the phosphate group changes the Synapsin protein’s shape and chemical properties. This modification decreases Synapsin’s affinity for both the synaptic vesicle membrane and the actin filaments of the cytoskeleton. This allows Synapsin to detach, freeing the reserve pool vesicles for mobilization and release.
Synapsin I is phosphorylated by PKA and CaMK I/IV at a conserved site (Site 1) and by CaMKII at two other sites (Sites 2 and 3). Mitogen-Activated Protein Kinase (MAPK) also targets Synapsin at additional sites. Phosphorylation by different kinases allows the neuron to finely tune the rate of vesicle mobilization in response to various signal patterns and intensities.
Synapsin’s Connection to Neurological Disorders
Dysfunction in the Synapsin protein family is linked to several neurological and psychiatric conditions. Mutations or altered expression levels in Synapsin genes disrupt the balance between excitatory and inhibitory signaling in the brain. This imbalance can lead to network hyperexcitability, a hallmark of certain disorders.
Synapsin I and Synapsin II gene mutations have been associated with increased susceptibility to epilepsy. Loss of Synapsin function can cause uncontrolled vesicle mobilization, leading to excessive and synchronized firing of neurons that manifests as seizures.
Synapsin II and Synapsin III have been implicated in schizophrenia and autism spectrum disorder (ASD). Decreased expression levels of these Synapsin types have been observed in patients with schizophrenia, suggesting a role in the synaptic changes seen in the disorder. Mutations in Synapsin genes have also been found in individuals with ASD, particularly those who also present with epilepsy.