Biochemical evidence accumulates across neurons to drive a network-level eruption

Thornquist, Stephen C.; Pitsch, Maximilian J.; Auth, Charlotte S.; Crickmore, Michael A.

doi:10.1016/j.molcel.2020.12.029

Cited by 19 publications

(23 citation statements)

References 66 publications

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“…However, we find it difficult to fit the 5-HT signal directly into this model, as activating the DPM neuron inhibits ACh release from KCs (Figure 4G-4L), and Gα/i-coupled 5-HT1a curbs the learning-related cAMP signal, both of which shorten the window. The other hypothesis is that the coincidence time window is biochemical, for example the CaMKII autophosphorylation activity, which also determines the copulation duration of Drosophila (Thornquist et al, 2020; Thornquist et al, 2021). It would then imply that 5-HT can somehow prolong the CaMKII autophosphorylation states.…”

Section: Discussionmentioning

confidence: 99%

Local 5-HT signal bi-directionally regulates the coincidence time window of associative learning

Zeng

Zhangren

et al. 2022

Preprint

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Temporal coincidence between the conditioned stimulus (CS) and unconditioned stimulus (US) is essential for associative learning across species. Despite its ubiquitous presence, the mechanism that may regulate this time window duration remains unclear yet. Using olfactory associative learning in Drosophila as a model, we find that suppressing or promoting serotonin (5-HT) signal could respectively shorten or prolong the coincidence time window of odor-shock associative learning and synaptic plasticity in mushroom body (MB) Kenyon cells (KCs). Capitalizing on GPCR-activation based (GRAB) sensors for 5-HT and acetylcholine (ACh), we characterized the in vivo 5-HT dynamics in MB lobes during odor and shock stimulations and further dissected this microcircuit. Interestingly, local KC-released ACh activates nicotinic receptors on the dorsal paired medial (DPM) neuron, and in turn the DPM neuron releases 5-HT to inhibit the ACh signal via the 5-HT1a receptor. Finally, we demonstrated that the DPM-mediated serotonergic feedback circuit is sufficient and necessary to regulate the coincidence time window. This work provides a model for studying the temporal contingency of environmental events and their causal relationship

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Section: Discussionmentioning

confidence: 99%

Local 5-HT signal bi-directionally regulates the coincidence time window of associative learning

Zeng

Zhangren

et al. 2022

Preprint

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“…Neuromodulators stably alter biochemical signaling to control persistent internal states Studies linking neuromodulator-induced biochemical signaling to internal states have been most extensive for the cAMP-PKA pathway. Fluorescent sensors of cAMP levels and PKA activation have revealed persistent increases in cAMP levels and downstream signaling with kinetics on the order of tens of seconds to minutes in freely moving flies (Thornquist et al, 2021) and mice (Lee et al, 2019;Zhang et al, 2021). These kinetics have been tied to internal state generation in several organisms.…”

Section: Reviewmentioning

confidence: 99%

“…One example is the set of Corazonin neurons in Drosophila, a small group of neurons controlling the animal's drive to copulate. Graded accumulation of cAMP in these neurons over minutes during successive activity bouts can trigger a synchronous burst of network activity, or eruption, that changes the motivational state of the fly such that its copulation drive is reduced (Thornquist et al, 2021). Optogenetic elevation of cAMP levels in Corazonin neurons can elicit this state transition.…”

Section: Reviewmentioning

confidence: 99%

The emergence and influence of internal states

Flavell¹,

Gogolla²,

Lovett-Barron³

et al. 2022

Neuron

119

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“…In particular, our transcriptomic data indicated that SETD1A haploinsufficiency leads to increased cAMP/PKA, which has been shown to enhance synaptic strength through different aspects, such as by modulating different ion channels (Anderson et al, 2000; Beaumont and Zucker, 2000; Connors et al, 2008; Gutierrez-Castellanos et al, 2017; Hell’ et al, 1995; van der Horst et al, 2020; Renner et al, 2017) and increasing neurite outgrowth (Aglah et al, 2008; Chu et al, 2006; Wan et al, 2011). Intriguingly, a recent study demonstrated that cAMP/PKA induces calcium influx through voltage-gated calcium channel, which pushes the neuronal network towards a large-scale and synchronized burst activity (Thornquist et al, 2021). Consistently, our calcium imaging data showed increased synchronized activity in SETD1A +/- networks, suggesting that there could be a similar cAMP-triggered mechanism in our model.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

Wang

Rhijn

Akkouh

et al. 2021

Preprint

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Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, have been shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. To study the effect of decreased SETD1A function in human cells, we generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was mainly characterized by an overly synchronized network. In individual neurons, this network phenotype was reflected by increased somatodendritic complexity and elevated synaptic connectivity. We found that this network phenotype was driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with schizophrenia, synaptic transmission and glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, using pharmacological experiments targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/- cultures. In conclusion, our results illuminate key molecular, cellular and network abnormalities caused by SETD1A haploinsufficiency and demonstrate a direct link between SETD1A and the cAMP-dependent pathway in human neurons.

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Biochemical evidence accumulates across neurons to drive a network-level eruption

Cited by 19 publications

References 66 publications

Local 5-HT signal bi-directionally regulates the coincidence time window of associative learning

Local 5-HT signal bi-directionally regulates the coincidence time window of associative learning

The emergence and influence of internal states

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

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