Regulation of Synapse Number and Synaptic Scaling

An important unanswered question in the field of neurodevelopment and regeneration is the following: How is synapse number and efficacy regulated? That is, how does a neuron "know" that it has acquired its full complement of synapses that would be required for functionality? It is hypothesized that the synaptic efficacy is regulated globally and enhances synaptic output nonselectively51,52. Alternatively, synaptic efficacy could also be modulated locally and selectively at specific synaptic sites40,53. Similarly, the number of synapses that any given neuron establishes could also be regulated either globally or locally. To this end, single isolated LPeDl-axons were paired with two identical presynaptic VD4 neurons. Electrophysiological recordings demonstrated that in this configuration only one VD4 formed synaptic connections with the isolated axon15. Since the isolated axon is devoid of its cell body, the synapse numbers are likely regulated locally by the axon itself. To address this issue further, we isolated a single, presynaptic neuron from the Lymnaea central ring ganglia and challenged it with two identical postsynaptic targets. Specifically, a single VD4 neuron was simultaneously soma-soma paired with two postsynaptic LPeD1 neurons. In the intact brain VD4 connects with only one LPeD1. Interestingly, under these experimental conditions only one postsynaptic cell received innervation from VD4 during the first 12-18 h of cell pairing. In contrast, when VD4 was paired with two different postsynaptic neurons, LPeDl and RPeDl, it formed excitatory and inhibitory synapses, respectively, with both neurons (Figure 2.3). Similarly, when the LPeD1-VD4-LPeDl triplet was examined during early stages of synapse formation (4 h), both LPeD1 cells were innervated by VD4. However, the efficacy of each individual synapse under these experimental conditions was a fraction of the monosynaptic strength exhibited among pairs and involved the cAMP-PKA-dependent pathway. Indeed, experimental activation of the cAMP-PKA pathway resulted in reduced synaptic efficacy, whereas inhibition of this cascade generated hyperinnervation and an enhancement of synaptic strength54. These data show that cAMP-PKA-dependent signaling plays a novel role in controlling synaptic efficacy and thus regulating single or multiple innervations. In mollusks, this may thus serve as one of the mechanisms that ensure a balance between neuronal input and output capacities.

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