Abstract
Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance.
Highlights
Among the hundreds of distinct cell types that make up our bodies, neurons are the most morphologically complex, and one of the most dynamic in their responsiveness and adaptability
Glutamate-gated channel opening of NMDA receptors enables calcium (Ca2+) influx into the dendritic spine, which initiates a cascade of signalling events involving the stimulation of the Ca2+/calmodulin-dependent protein kinase (CaMK) as well as the extracellular signal regulated kinase (ERK)
Knowledge of how the nucleus computes action potentials to promote gene transcription while avoiding background stimulation is fundamental for understanding how synaptic inputs regulate activity-dependent gene transcription and neuronal plasticity. Conclusion it has been known for more than 25 years that gene induction upon excitatory transmission is a required step for neuronal plasticity, it is not yet clear whether a direct link between local synaptic activation and gene transcription exists
Summary
Among the hundreds of distinct cell types that make up our bodies, neurons are the most morphologically complex, and one of the most dynamic in their responsiveness and adaptability. NMDARs appeared to have a role in the activation of nuclear events through their contribution to action potential generation[122] These results led to a third model proposed by Dudek and colleagues, which posits that the robust depolarisation of the somatic plasma membrane is sufficient to induce gene transcription without the involvement of transported biochemical signals from distant synapses[71,72,123]. It is well established that membrane depolarisation in the soma causes the opening of voltage-gated Ca2+ channels (VGCCs), which allow the influx of Ca2+ from the extracellular space to the cytoplasm, coupling synaptic activity to intracellular signalling[14,131] It appears that, among the different classes of VGCCs, L-type VGCCs seem to be significantly involved in regulating transcription since activity-dependent induction of genes is supressed by exposure to specific antagonists and increased by (-)BayK-8644, a VGCC agonist[14,132,133]. Knowledge of how the nucleus computes action potentials to promote gene transcription while avoiding background stimulation is fundamental for understanding how synaptic inputs regulate activity-dependent gene transcription and neuronal plasticity
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