Widespread posttranscriptional regulation of cotransmission

Abstract

While neurotransmitter identity was once considered singular and immutable for mature neurons, it is now appreciated that one neuron can release multiple neuroactive substances (cotransmission) whose identities can even change over time. To explore the mechanisms that tune the suite of transmitters a neuron releases, we developed transcriptional and translational reporters for cholinergic, glutamatergic, and GABAergic signaling in Drosophila . We show that many glutamatergic and GABAergic cells also transcribe cholinergic genes, but fail to accumulate cholinergic effector proteins. Suppression of cholinergic signaling involves posttranscriptional regulation of cholinergic transcripts by the microRNA miR-190; chronic loss of miR-190 function allows expression of cholinergic machinery, reducing and fragmenting sleep. Using a “translation-trap” strategy, we show that neurons in these populations have episodes of transient translation of cholinergic proteins, demonstrating that suppression of cotransmission is actively modulated. Posttranscriptional restriction of fast transmitter cotransmission provides a mechanism allowing reversible tuning of neuronal output.

An integrative sensor of body states: how the mushroom body modulates behavior depending on physiological context

“…Additional fascinating avenues for future investigation include potential adaptations in the firing mode of neurons of the input layer in response to external or physiological signals (similarly to neurons encoding tiredness in the CC; Liu et al 2016 ), and differential responses of downstream layers due to state-dependent changes in receptor expression and trafficking ( Yamamoto and Seto 2014 ; Pribbenow et al 2022 ). Bearing in mind that dopaminergic and other neuron types can release multiple neurotransmitters and are involved in promoting several behaviors (e.g., serotonergic and GABAergic DPMs promoting sleep and social approach) ( Haynes et al 2015 ; Aso et al 2019 ; Sun et al 2020 ; Yamazaki et al 2023 ), it would be also interesting to explore potential context- and state-dependent alterations in cotransmission and their implications on behavior ( Chen et al 2023 ).…”

Translational regulation enhances distinction of cell types in the nervous system

“…Consistent with this idea, our UAS-Rh1-Venus reporter showed heterogeneous expression even among neurons, contrasting with the more uniform expression observed in the control UASz-GFP reporter ( Figure 5E , Figure 5—figure supplement 1B and C ). In accordance, choline acetyltransferase (ChAT), an enzyme needed to synthesize acetylcholine, and vesicular acetylcholine transporter (VAChT) are transcribed in many glutamatergic and GABAergic neurons but its protein synthesis is inhibited ( Chen et al, 2023 ; Lacin et al, 2019 ). Substantial post-transcriptional regulations are also implicated during development ( Li et al, 2020 ; Zhang et al, 2016 ).…”

Translational regulation enhances distinction of cell types in the nervous system

“…Consistent with this idea, our UAS-Rh1-Venus reporter showed heterogeneous expression even among neurons, contrasting with the more uniform expression observed in the control UASz-GFP reporter (Figures 5E and Figure 5 – figure supplement 1B-C). In accordance, choline acetyltransferase (ChAT), an enzyme needed to synthesize acetylcholine, and vesicular acetylcholine transporter (VAChT) are transcribed in many glutamatergic and GABAergic neurons but its protein synthesis is inhibited (Chen et al, 2023; Lacin et al, 2019). Substantial post-transcriptional regulations are also implicated during development (Li et al, 2020; Zhang et al, 2016).…”