Dataset Information

Compound-Induced Neuroplasticity Without Immediate Early Gene Activation

ABSTRACT: Cortical atrophy and dysfunction are hallmarks of many neuropsychiatric diseases including depression, post-traumatic stress disorder (PTSD), and addiction. Psychoplastogens are small molecules with the potential to rapidly rescue these structural and functional deficits, leading to sustained therapeutic effects after a single administration. Classic psychedelics are among the most potent and efficacious psychoplastogens known, with recent data indicating that their clinical and preclinical effects might be more robust and durable than those of ketamine. Moreover, the advent of non-hallucinogenic psychoplastogens structurally related to psychedelics, such as tabernanthalog (TBG), has opened new opportunities for developing scalable alternatives capable of promoting structural and functional neuroplasticity in the prefrontal cortex (PFC). Currently, it is unclear what roles 5-HT2A receptors (5-HT2ARs) and immediate early gene activation play in the neuroplasticity-promoting effects of non-hallucinogenic psychoplastogens like TBG—information necessary to engineer optimized neurotherapeutics related to psychedelics. Here, we use a combination of pharmacological and genetic tools to demonstrate that several non-hallucinogenic psychoplastogens promote cortical neuron growth through the same biochemical pathway as classic psychedelics. Furthermore, we demonstrate that there is a causal relationship between TBG-induced cortical spinogenesis and its sustained antidepressant-like effects. In contrast to psychedelics, TBG promotes cortical neuron growth in the absence of a glutamate burst or immediate early gene (IEG) activation, effects assumed to be necessary for psychedelic-induced neuroplasticity. Our results elucidate how the hallucinogenic effects of psychedelics can be decoupled from their beneficial effects on cortical neuron growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE277053 | GEO | 2025/05/10

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.

Dataset Information

Compound-Induced Neuroplasticity Without Immediate Early Gene Activation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets