David Colameo

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Colameo

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David

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0000-0001-8432-9396

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Publications 1 - 6 of 6

microRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity
Colameo, David; Maley, Sara M.; Winterer, Jochen; et al. (2025)
Proceedings of the National Academy of Sciences of the United States of America
Homeostatic synaptic plasticity (HSP) is a neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of microRNA-binding sites in genes changing upon PTX-induced HSD, we bioinformatically predict and experimentally validate increased miR-218-5p activity upon PTX treatment. By electrophysiological recordings and confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: It occludes the downscaling of excitatory synapses and dendritic spines, while at the same time attenuating inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a direct miR-218-5p target which potentially mediates the effect of miR-218-5p on homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic recordings, we further reveal that local inhibition of miR-218-5p in the somatosensory cortex reduces local slow-wave activity during non-rapid-eye-movement sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with implications for pathophysiology.
miR-329- and miR-495-mediated Prr7 down-regulation is required for homeostatic synaptic depression in rat hippocampal neurons
Inouye, Michiko O.; Colameo, David; Ammann, Irina; et al. (2022)
Life Science Alliance
Homeostatic synaptic depression (HSD) in excitatory neurons is a cell-autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that proline-rich protein 7/transmembrane adapter protein 3 (Prr7) down-regulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329- and miR-495-mediated Prr7 reduction upstream of the CDK5-SPAR pathway.
The Role of Posttranscriptional Gene Regulation During Homeostatic Synaptic Plasticity
Colameo, David (2023)
Homeostatic synaptic plasticity (HSP) is a vital mechanism in neural networks, enabling neurons to adapt their firing rates and synaptic strength to chronic changes in activity. This process is crucial not only for maintaining stable brain function but also for contributing to memory consolidation during sleep. However, the molecular mechanisms underlying HSP remain complex and multifaceted. This thesis integrates insights from two research papers to shed light on the intricate interplay of gene expression regulation and miRNA-mediated coordination during activity-dependent HSP. In the first paper, we conducted a comprehensive multi-omics characterization of gene expression in primary hippocampal neurons undergoing picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD). Our investigation revealed compartment-specific alterations in the transcriptome and proteome, with regulators of neuronal excitability predominantly downregulated in the somatic compartment and structural components of excitatory postsynapses primarily affected in processes. Local inhibition of protein synthesis in processes during scaling was confirmed for synaptic proteins, highlighting the role of compartmentalized gene expression changes in synaptic computation and homeostasis. The second paper explored the role of miR-218-5p in regulating inhibitory and excitatory synapses during HSD in primary hippocampal neurons. Through bioinformatic predictions and experimental validation, we identified increased miR-218-5p activity in the process compartment upon PTX treatment. Functionally, miR-218-5p exhibited a dual effect during HSD, preventing the downscaling of excitatory synapses and dendritic spines while blocking inhibitory synapse upscaling. Additionally, we identified Mdga1 as a target of miR-218-5p in the context of inhibitory synapse upscaling. Furthermore, our in vivo EEG recordings demonstrated that local inhibition of miR-218-5p in the mouse brain impacted sleep homeostasis, emphasizing the role of miR-218-5p in regulating HSD during sleep. In summary, this thesis uncovers the intricate mechanisms of HSP, highlighting the interplay between compartmentalized gene expression changes and miRNA-mediated coordination. These findings contribute to a deeper understanding of neural circuit stability in response to activity-induced perturbations, with potential implications for both physiological and pathological conditions.
Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling
Colameo, David; Rajman, Marek; Soutschek, Michael; et al. (2021)
EMBO Reports
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 perform a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. We uncover both highly compartment-specific and correlating changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurs primarily in the somatic compartment, structural components of excitatory postsynapses are mostly downregulated in processes. Local inhibition of protein synthesis in processes during scaling is confirmed for candidate synaptic proteins. 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, during synaptic scaling, compartmentalized gene expression changes might co-exist with neuron-wide mechanisms to allow synaptic computation and homeostasis.
Synaptic tagging: homeostatic plasticity goes Hebbian
Colameo, David; Schratt, Gerhard (2022)
The EMBO Journal
Distinct plasticity mechanisms enable neurons to effectively process information also when facing global perturbations in network activity. In this issue of The EMBO Journal, Dubes et al (2022) provide a molecular mechanism whereby individual synapses during periods of chronic inactivity are "tagged" for future strengthening. These results lend further support to the idea that local, nonmultiplicative mechanisms play an important role in homeostatic synaptic plasticity as has been demonstrated for Hebbian-like synaptic plasticity.
Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia
Cramer, Teresa; Gill, Raminder; Thirouin, Zahra S.; et al. (2022)
Science Advances
Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75NTR) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.

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David Colameo

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