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A recent study by Vardalaki, et al. demonstrates a substantial amount of filopodia in deep layer V pyramidal cells of the adult visual cortex, are silent synapses [1]. Filopodia are found to lack AMPAreceptor- mediated transmission, but they exhibit NMDA-receptormediated synaptic transmission. They could be “unsilenced” by spiketiming protocol which induces Long-Term Potentiation (LTP). These results suggest that silent synapses that are sensitive to LTP recruitment exist in adult cortical neurons, and filopodia can serve as a marker for silent synapses in the adult brain.

Silent synapses and their contribution to LTP

Silent synapses were first discovered in young hippocampal neurons in the hippocampal CA1 region and spinal cord dorsal horn [2-5]. They have been defined as the synapses that lack functional receptors of presynaptic neurotransmitters [2,6,7]. In addition to the hippocampus, studies demonstrated that silent synapses exist in the developing cortices [8,9]. Interestingly, recent studies using MED-64 recording channels found that some silent responses can be detected in the adult Anterior Cingulate Cortex (ACC) after applying the LTPinducing protocol [10-13]. Such recruitment of silent responses may be due to the recruitment of silent synapses. Future studies are clearly needed to examine such a possibility.

The signaling pathway of the silent synapse is similar to that in chronic pain

Previous studies of the intracellular mechanism of ACC-LTP and chronic pain provide a possible explanation for the basic mechanisms of the recruitment of silent synapses. In addition to the potentiation of existing AMPA receptor-mediated responses, the recruitment of silent synapses also serves as a key mechanism for a postsynaptic form of LTP in the ACC. Genetic and pharmacological findings indicate that calcium calcium-stimulated Adenylyl Cyclase subtype 1 (AC1) or AC1 activity is required for the recruitment of silent responses in the ACC [11-13]. Activation of NMDA receptors increases postsynaptic Ca²⁺ which increases second messenger cAMP and then leads to activation of PKA, and the phosphorylation of AMPA receptors by PKA plays important roles in the potentiation of AMPA receptor receptormediated responses as well as the recruitment of silent responses [10,11]. In addition, PKMζ activity and Fragile X Mental Retardation Protein (FMRP) may also be required [11].

In addition to the NMDA receptor-dependent silent synapse, serotonin can trigger activation of silent synapses between some primary sensory afferents and dorsal horn neurons in the spinal cord by recruiting AMPA receptors. This activation of silent synapses requires protein interactions involving the GluR2/3 C-terminus as well as PKC [5].

Functional implications for adult silent synapses in chronic pain and emotion

Cortical excitation or potentiation has been proposed to contribute to chronic pain and pain-related anxiety [14-19]. Silent synapses add new mechanisms for critical potentiation/excitation in adult animals. Furthermore, the recruitment of silent synapses may lay the basis for spreading the excitation within the cortical circuit and cortical-related connections. For example, the reciprocal connection between the ACC and Basolateral Amygdala (BLA) may lay the foundation of chronic pain-related emotional disorders. It is important to understand possible different mechanisms or molecules that may be involved, and this new information may help us to find better treatment for patients with chronic pain and its related emotional disorders

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