Assens, A. | bioRxiv Science

bioRxiv2026

Deletion of TNFR1 in astrocytes restores memory in aged Alzheimer's disease mice

Astrocytes participate in local inflammation and cognitive decline in Alzheimers disease (AD). Aberrant cytokine TNF signaling via astrocyte type-1 receptor (aTNFR1) could causally link the two AD pathology aspects. To verify this hypothesis, we crossed transgenic AD mice with mice enabling astrocyte-specific conditional TNFR1 deletion (aTNFR1KO). Induction of aTNFR1KO at early AD stages, preserved memory and reduced {beta}-amyloid load and astrogliosis in the aged mice. Induction of aTNFR1KO at late AD stages, in mice already memory-impaired, surprisingly produced rapid memory rescue, without affecting {beta}-amyloid load and astrogliosis. Single nucleus-RNA-seq analysis of all hippocampal cell populations revealed that late-stage aTNFR1KO rapidly modifies gene expression mainly in neurons, primarily targeting synaptic pathways, causing combined glutamatergic downregulation and GABAergic up-regulation. Consistently, hippocampal EEGs showed a pro-inhibitory effect of aTNFR1KO, which thus restores memory by "rebalancing" hippocampal circuitry excitability. This pro-memory effect identifies a new mechanism and astrocyte target against cognitive decline in AD.

neuroscience↗

bioRxiv2021

Transcriptional adaptation of sensory neurons to GPCR identity and activity

Sensory adaptation is critical to extract information from a changing world. Taking advantage of the extensive parallel coding lines present in the olfactory system, we explored the potential variations of neuronal identities before and after olfactory experience. We found that at rest, the transcriptomic profiles of olfactory sensory neuron populations are already highly divergent, specific to the olfactory receptor they express, and are surprisingly associated with the sequence of these latter. These divergent profiles further evolve in response to the environment, as odorant exposure leads to massive reprogramming via the modulation of transcription. Adenylyl cyclase 3, but not other main elements of the olfactory transduction cascade, plays a critical role in this activity-induced transcriptional adaptation. These findings highlight a broad range of sensory neuron identities that are present at rest and that adapt to the experience of the individual, thus providing a novel layer of complexity to sensory coding.

neuroscience↗