Cholinergic Synaptic Homeostasis Is Tuned by an NFAT-Mediated α7 nAChR-Kv4/Shal Coupled Regulatory System

Abstract

SUMMARY Homeostatic synaptic plasticity (HSP) involves compensatory mechanisms employed by neurons and circuits to preserve signaling when confronted with global changes in activity that may occur during physiological and pathological conditions. Cholinergic neurons, which are especially affected in some pathologies, have recently been shown to exhibit HSP mediated by nicotinic acetylcholine receptors (nAChRs). In Drosophila central neurons, pharmacological blockade of activity induces a homeostatic response mediated by the Drosophila α7 (Dα7) nAChR, which is tuned by a subsequent increase in expression of the voltage-dependent K v 4/Shal channel. Here, we show that an in vivo reduction of cholinergic signaling induces HSP mediated by Dα7 nAChRs, and this upregulation of Dα7 itself is sufficient to trigger transcriptional activation, mediated by nuclear factor of activated T cells (NFAT), of the K v 4/Shal gene, revealing a receptor-ion channel system coupled for homeostatic tuning in cholinergic neurons.

Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse development in Drosophila

“…Whether this is true for central cholinergic synapses is not known. Although adaptive plasticity clearly occurs in the Drosophila CNS and it is conceivable that Hebbian forms of plasticity also play a role in regulating the structure and function of cholinergic synapses, our findings suggest that homeostatic, rather than Hebbian, plasticity is the main force steering LNv's developmental progression and tuning its synaptic transmission, consistent with findings from a number of recent studies in the Drosophila CNS (52,64,65). With newly developed genetic reagents, transcriptome and connectome information, and an increasing number of physiological studies, we believe this question will be answered in the near future.…”

“…Lastly, although it is tempting to assert that the modulation of Dα1 and Dα6 expression results solely from transcriptional control based on the clear developmental shifts in their transcript levels, our work did not rule out the involvement of posttranslational regulatory steps, which may influence the folding, processing, and synaptic integration of nAchR subunits during cholinergic synapse development. A number of nAchR-associated accessory proteins, such as RIC-3, 14-3-3 proteins, LRP4, and Nacho, have been identified in vertebrate, Caenorhabditis elegans, and/or Drosophila systems (21,45,46,(49)(50)(51)(52) and deserve attention in future work for roles they play in ensuring the correct expression and function of Dα1-and Dα6-containing receptor subtypes.…”

Postsynaptic plasticity of cholinergic synapses underlies the induction and expression of appetitive memories in Drosophila

“…As, comparable to vertebrate systems, α7 also plays a significant role at presynaptic neurites 39 , we did not follow up on this observation in this study.…”

Constructing and Tuning Excitatory Cholinergic Synapses: The Multifaceted Functions of Nicotinic Acetylcholine Receptors in Drosophila Neural Development and Physiology

“…These results demonstrated the inhibition-triggered homeostatic upregulation of synaptic activity and how it is balanced by the enhancement of the hyperpolarizing K + currents ( Ping and Tsunoda, 2011 ). These findings were replicated in vivo through genetic manipulation of cholinergic activity ( Eadaim et al, 2020 ), which also implicated the role of transcription factor NFAT that acts as the intermediate linking increased Dα7-dependent synaptic transmission with Shal upregulation.…”

“…As mentioned in previous sections, plasticity is a widespread occurrence at cholinergic synapses, and in some cases, is strongly tied to post-translational events ( Figure 4 ). A great example is related to the case we discussed earlier: inhibition of nAchR-mediated cholinergic activity which drives the transcription-independent increase in Dα7-mediated currents, ( Ping and Tsunoda, 2011 ; Eadaim et al, 2020 ). The observation that overexpressing the nAchR-associated chaperone NACHO alone can enhance this homeostatic response indicates that post-translational processes can also elevate cholinergic transmission even when total nAchR protein levels remain constant.…”