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Physiological Roles of Endocytosis and Presynaptic Scaffold in Vesicle Replenishment at Fast and Slow Central Synapses


Core Concepts
Endocytosis-driven release site clearance and presynaptic scaffold-mediated vesicle replenishment cooperatively maintain synaptic strength and enable high-fidelity neurotransmission at fast-signaling synapses, while endocytosis-dependent site clearance boosts short-term synaptic facilitation at slow-plastic synapses.
Abstract
The content examines the physiological significance of endocytosis and presynaptic scaffold mechanisms in regulating synaptic transmission and plasticity at fast-signaling brainstem calyceal synapses and slow-plastic hippocampal CA1 synapses. Key highlights: At the calyx of Held, a fast-signaling relay synapse, pharmacological block of endocytosis or presynaptic scaffold activity enhanced synaptic depression during high-frequency stimulation (100 Hz) by rapidly clearing release sites and replenishing vesicles, respectively. The endocytosis-dependent site clearance mechanism operated in an activity-dependent manner, while the scaffold-mediated vesicle replenishment was activity-independent, suggesting a complementary role of the two mechanisms in maintaining synaptic strength and enabling high-fidelity neurotransmission at fast synapses. At hippocampal CA1 synapses, which exhibit short-term facilitation, endocytic blockers attenuated synaptic facilitation, indicating that endocytosis-dependent site clearance boosts short-term synaptic potentiation, potentially facilitating the induction of long-term potentiation underlying memory formation. In contrast, presynaptic scaffold inhibitors had no effect on short-term plasticity at hippocampal CA1 synapses, suggesting that the scaffold machinery plays a specialized role in vesicle replenishment predominantly at fast-signaling synapses.
Stats
Endocytic blockers Dynasore and Pitstop-2 inhibited fast endocytosis at the calyx of Held by reducing the endocytic rate from ~350 fF/s to ~150 fF/s. Endocytic blockers enhanced synaptic depression during 100 Hz stimulation at the calyx of Held, increasing the steady-state depression from 58% to 75%. Scaffold protein inhibitors ML141 and Latrunculin-B enhanced synaptic depression during 100 Hz stimulation at the calyx of Held, increasing the steady-state depression from 58% to 80%. Endocytic blockers attenuated synaptic facilitation during 10 Hz and 25 Hz stimulation at hippocampal CA1 synapses.
Quotes
"Endocytic and scaffold proteins are thought to underlie this mechanism. However, physiological significance of the site-clearance mechanism among diverse central synapses remains unknown." "At the calyx of Held, in slices from pre-hearing rats, pharmacological block of endocytosis slightly enhances STD and markedly prolongs the recovery from STD (Hosoi et al., 2009)." "Genetic ablation of the endocytic adaptor protein AP-2μ (Jung et al., 2015), synaptophysin (Rajappa et al., 2016), or the secretory carrier membrane protein SCAMP5 (Park et al., 2018) enhances synaptic depression in cultured cells, in agreement with the site-clearance role of endocytosis."

Deeper Inquiries

How do the endocytosis-dependent and scaffold-dependent mechanisms for vesicle replenishment interact and coordinate at synapses that exhibit both fast signaling and long-term plasticity, such as the mossy fiber-CA3 synapses in the hippocampus?

At synapses like the mossy fiber-CA3 synapses in the hippocampus that exhibit both fast signaling and long-term plasticity, the endocytosis-dependent and scaffold-dependent mechanisms for vesicle replenishment likely interact and coordinate to ensure efficient neurotransmission and synaptic plasticity. Endocytosis plays a crucial role in clearing release sites of vesicular residues and facilitating the rapid replenishment of transmitter-filled vesicles. This process is essential for maintaining synaptic strength during high-frequency transmission and counteracting synaptic depression caused by vesicle depletion. On the other hand, the presynaptic scaffold machinery, including proteins like intersectin and CDC42, is involved in regulating the assembly of F-actin and facilitating the rapid translocation of new vesicles to release sites. This scaffold-dependent mechanism likely contributes to the rapid replenishment of vesicles, especially at fast-signaling synapses. In synapses with both fast signaling and long-term plasticity, such as mossy fiber-CA3 synapses, the coordination between endocytosis and the presynaptic scaffold machinery is crucial for balancing short-term synaptic efficacy and long-term plasticity. Endocytosis may support the rapid replenishment of vesicles during high-frequency transmission, while the scaffold machinery may play a role in maintaining synaptic strength and facilitating synaptic plasticity. The interaction between these two mechanisms ensures efficient neurotransmission and the dynamic regulation of synaptic strength and plasticity at these synapses.

What are the potential compensatory mechanisms that may arise in response to genetic ablation of endocytic or scaffold proteins, and how do these differ from the acute pharmacological inhibition used in this study?

Genetic ablation of endocytic or scaffold proteins may lead to the activation of compensatory mechanisms to maintain synaptic function and neurotransmission. In the case of genetic ablation, the absence of a specific protein may trigger adaptive changes in the expression or function of other proteins or signaling pathways to compensate for the loss of the targeted protein. These compensatory mechanisms may involve upregulation of alternative endocytic pathways, changes in the expression of other synaptic proteins, or alterations in presynaptic release machinery to maintain synaptic efficacy. On the other hand, acute pharmacological inhibition used in this study provides a more immediate and direct way to assess the specific role of endocytosis or scaffold proteins in synaptic function. By acutely blocking these proteins with pharmacological inhibitors like Dynasore or Pitstop-2, the study can elucidate the acute effects of disrupting these mechanisms on synaptic transmission without the confounding factors of compensatory changes that may occur with genetic ablation. This approach allows for a more precise and controlled investigation of the immediate impact of endocytosis or scaffold protein inhibition on synaptic function.

Could the specialized roles of endocytosis and presynaptic scaffold machinery in regulating synaptic transmission and plasticity be leveraged to selectively modulate information processing in neural circuits involved in different cognitive functions, such as sensory processing versus memory formation?

The specialized roles of endocytosis and presynaptic scaffold machinery in regulating synaptic transmission and plasticity offer promising opportunities to selectively modulate information processing in neural circuits involved in different cognitive functions, such as sensory processing and memory formation. By targeting these mechanisms, it may be possible to fine-tune synaptic strength, plasticity, and neurotransmission in specific neural circuits to enhance or suppress certain cognitive functions. For example, modulating endocytosis at fast-signaling synapses involved in sensory processing could enhance the efficiency of neurotransmission and improve sensory information processing. On the other hand, targeting the presynaptic scaffold machinery at synapses involved in memory formation could facilitate synaptic plasticity and strengthen memory encoding and retrieval processes. By selectively manipulating these mechanisms, it may be possible to optimize neural circuit function for specific cognitive tasks and potentially develop novel therapeutic strategies for neurological disorders affecting sensory processing or memory formation.
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