Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

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.

Figure 1.. Synapto-nuclear translocation of transcription regulators.

a) In non-stimulated conditions, transcription regulators (TR, purple dots) are localised into distant dendrites as well as at the perinuclear zone. Some TRs are transported from the cytoplasm to the nucleus by importins (orange dots). Importins are also distributed across distant dendrites and at the postsynaptic density (PSD). b, c) Excitatory inputs that stimulate synapses (1) are believed to activate TRs, which are then transported to the soma along the neuron (2) through microtubule-based active transport b) or by passive diffusion c). Excitatory inputs are also proposed to activate importins at the PSD, which then associate to synaptic cargoes and facilitate their synapto-nuclear translocation c). Therefore, this model predicts that synaptic activity triggers the accumulation of TRs from distant synapses in the nucleus, promoting the induction of gene expression programs (3).

Figure 2.. Calcium signal propagation from the synapse to the nucleus.

The endoplasmic reticulum (ER) is distributed throughout the cytoplasm from the nuclear envelope to dendritic spines. Excitatory synaptic stimulation through glutamate causes membrane depolarisation and entry of Ca ²⁺ (blue dots) from the extracellular space through NMDARs (1). Moreover, glutamate also activates mGluRs coupled to PLC thereby stimulating IP ₃ production (green dots). Ca ²⁺ and IP ₃ stimulate receptors present at the ER membrane that open and release more Ca ²⁺ from the ER lumen, establishing a Ca ²⁺-induced Ca ²⁺-release wave (2) that propagates from dendrites towards the soma. In the soma, Ca ²⁺ release from the ER activates cytoplasmic Ca ²⁺-dependent signalling cascades that convey the signal to the nucleus (3). Moreover, Ca ²⁺ can be released to the nucleus from the ER, where it activates nuclear transcription regulators (4).

Figure 3.. Activation of nuclear functions by action potentials.

Excitatory synaptic activity (arrowheads) generates local changes in membrane conductance, which causes the opening of voltage gated calcium channels (VGCCs). A rise in intracellular Ca ²⁺ triggers the local activation of Ca ²⁺-dependent signalling pathways thereby, coupling membrane depolarisation to intracellular signalling. a) When neurons receive weak excitatory inputs (small arrowheads), the signal spread is small (thin solid arrows) and the threshold to trigger action potentials is not reached, thus somatic L-VGCCs remain closed. b) When neurons receive strong synaptic inputs (big arrowheads), dendritic spikes can efficiently spread (thick solid arrows) in the forward direction and facilitate the initiation of action potentials at the axonal initial segment. Action potentials are backpropagated to the soma and dendrites (dashed arrows), locally generate intracellular Ca ²⁺-dependent signalling cascades. Ca ²⁺ entry in the soma through L-VGCCs will promote the activation of protein effectors that regulate the transcription of plasticity-related genes. In this diagram, the local signal intensity representing both the electrical activity of the membrane and its coupled intracellular signalling is coded by colour. Drawings are adapted from a reconstructed biocytin-filled layer V neuron in the rat cortex (courtesy of B. Chieng and J. Bertran-Gonzalez).