Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling

Abstract

Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell-wide mechanisms is controversial. Here we performed a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. Thereby, we uncovered both highly compartment-specific and correlated changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurred primarily in the somatic compartment, structural components of excitatory postsynapses were mostly downregulated in processes. Motif analysis further suggests an important role for trans-acting post-transcriptional regulators, including RNA-binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that compartmentalized gene expression changes are widespread in synaptic scaling and might co-exist with neuron-wide mechanisms to allow synaptic computation and homeostasis.

Synaptic tagging: homeostatic plasticity goes Hebbian

“…Moreover, it will be interesting to test whether similar mechanisms are engaged in other homeostatic processes, such as synaptic downscaling. Interestingly, SP seems to be downregulated in the synaptodendritic compartment during picrotoxin‐induced homeostatic synaptic downscaling (Colameo et al , 2021), consistent with a bidirectional regulatory role in HSP. Many miRNAs have been assigned important roles in HSP and local translation at synapses, and it is therefore tempting to speculate that miRNAs might have a more general role in the input‐specific control of HSP.…”

Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

“…It is 66% conserved at the amino acid level between human and zebrafish (Hu et al, 2011) and is highly expressed early in development (Alliance of Genome Resources, 2020), likely explaining the developmental phenotype observed in our larval model. ARFGAP2 has not been extensively studied in the context of behavioral characteristics; however, it has been associated with synaptic plasticity (Colameo et al, 2021;Zhang et al, 2012) and neurocognitive disorders including depression (Nagel et al, 2018) and Alzheimer's disease (Gouveia et al, 2022), which are both associated with disrupted sleep. The zebrafish harboring mutations in arfgap2 appeared normal through early development (1-2 days post fertilization); however, by the third day, approximately half of the larvae began to appear abnormal with a curved tail.…”