Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3

Abstract

Synaptic receptors gate the neuronal response to incoming signals, but they are not homogeneously distributed on dendrites. A spatially defined receptor distribution can preferentially amplify certain synaptic inputs, resize receptive fields of neurons, and optimize information processing within a neuronal circuit. Thus a longstanding question is how the spatial organization of synaptic receptors is achieved. Here we find that action potentials provide local signals that influence the distribution of synaptic AMPA receptors along dendrites in mouse cerebellar stellate cells. Graded dendritic depolarizations elevate CPEB3 protein at proximal dendrites where we suggest that CPEB3 binds to GluA2 mRNA suppressing GluA2 protein synthesis leading to a distance-dependent increase in synaptic GluA2 AMPARs. The activity-induced expression of CPEB3 requires increased Ca2+ and PKC activation. Our results suggest a cell-autonomous mechanism where sustained postsynaptic firing drives graded local protein synthesis thus directing the spatial organization of synaptic AMPARs.

Three-dimensional Ca 2+ imaging advances understanding of astrocyte biology

“…Certain brain areas are denervated by slice preparation, paradoxically resulting in sPSC frequency being equal to mPSC frequency in TTX. This situation is seen for instance in the cerebellar cortex (58,59) and is likely present also in cortical slices with e.g. transected thalamic afferents.…”

Studying Axon-Astrocyte Functional Interactions by 3D Two-Photon Ca2+ Imaging: A Practical Guide to Experiments and “Big Data” Analysis

“…Even moving the stimulation electrode by a few μm sideways has different consequences in the two cases, as it will generally drastically increase the failure rate in the cerebellum, but not in the hippocampus. This characteristic of the cerebellar parallel fibers is well-known and exploited in the field (see e.g., Sullivan et al, 2005 ; Gao et al, 2006 ; Soler-Llavina and Sabatini, 2006 ; Abrahamsson et al, 2012 ; Savtchouk et al, 2016 ). Several studies have successfully demonstrated the targeted, spatially restricted nature of such stimulation using either Ca 2+ imaging in the stellate cell dendrites (see e.g., Figure 8 in Soler-Llavina and Sabatini, 2006 ) or optical detection of extracellular glutamate released upon parallel fiber stimulation (e.g., Figure 2 of Okubo et al, 2010 ), even when stimulating with very large current strength.…”

“…A running average of each colored trace is displayed in black. Traces interval corresponds to 1,200 time-frames (complete Z-stacks) acquired in 440 s. Stimulation protocol as in (Bindocci et al, 2017 ) but sped up twice (Savtchouk et al, 2016 ): single pulse or paired/train stimulations (100 Hz) are delivered once every 10 s in the following sequence: 1, 2, 3, 4, 5, 1, 2 pulses. The three stimulation epochs are separated by quiescent intervals.…”

“…Thus, the myelin sheath itself can act as a potent dielectric insulator, reducing the direct effects of the currents and the capacitive coupling of the axon to the voltage transients. For instance, local, targeted activation of the parallel fibers (unmyelinated axons) can be achieved by ejecting minimal currents (1–4 μA typical, Sullivan et al, 2005 ; Savtchouk et al, 2016 ), while stimulation current needs to be increased by one order of magnitude in the dentate gyrus (Di Castro et al, 2011 ; Bindocci et al, 2017 ). Even moving the stimulation electrode by a few μm sideways has different consequences in the two cases, as it will generally drastically increase the failure rate in the cerebellum, but not in the hippocampus.…”

Role of CPEB3 protein in learning and memory: new insights from synaptic plasticity

“…For example, action potentials (APs) regulate CPEB3 expression by activating protein kinase C (PKC) via Ca 2+ entry through voltage-gated Ca 2+ channels. Once PKC is activated, it is translocated to the plasma membrane it mediates the post-synaptic activity dependent regulation of CPEB3 as demonstrated by PKC inhibitors [ 77 ]. Disruption of CPEB3-GluA2 mRNA interaction increases synaptic GluA2 expression at proximal synapses, indicating that CPEB3-GluA2 mRNA interactions may be responsible for the dendritic GluA2 gradient that fine-tunes the neuronal response to incoming signals.…”