Sodergren, M. | bioRxiv Science

bioRxiv2025

GABA-induced Ca2+ signaling in the primary cilium of neurons

The complex signaling processing in neurons requires establishment of autonomous compartments. The compartment that is unique for neurons and crucial for neuron-neuron signaling is the synapse. Another compartment, that neurons share with all other cells in the body, is the primary cilium. The primary cilium is a solitary organelle, present in almost every neuronal cell type, that extends into the extracellular space for detection of signals. Several GPCRs have been identified as ciliary receptors, and here we show that the metabotropic GABA receptor subtype 1 localizes to primary cilia of neurons across different regions of the mouse brain and that activation of these receptors initiates Ca2+ signaling that is restricted to this organelle. The excitatory nature of GABAergic signaling in primary cilia is opposite to GABA action in other neuronal domains, indicating distinct modes of action of this universal inhibitory neurotransmitter even within the same neuron.

neuroscience↗

bioRxiv2023

Effect of ketamine on early synaptic mistuning and emotional behavior deficits in AppNL-F mouse model of Alzheimer's disease.

Alzheimers disease is the most common neurodegenerative disease and constitute 75% of dementia cases worldwide. Unfortunately, efficient and affordable treatments are still lacking for this mental illness, it is therefore urgent to identify new pharmacological targets. Whereas the late phases of the disease are well described, recent evidence suggest synaptic impairments at a pre-amyloid {beta} (A{beta}) plaque stage. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in Alzheimers disease, especially around A{beta} plaques. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of Alzheimers disease. In this study we used the AppNL-F knock-in mouse model of Alzheimers disease which carries two disease-causing mutations inserted in the amyloid precursor protein (App) gene. This strain does not start to develop A{beta} plaques until nine months of age. To better understand early changes in Alzheimers disease, we investigated synaptic function, at both neuronal and astrocytic levels, in six months old AppNL-F mice and correlate the synaptic dysfunction with emotional behavior. Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B (MAO-B) blocker deprenyl or the fast-acting antidepressant ketamine (5mg/kg). Thus, we propose that reactive astrocytes can induce synaptic mistuning early in Alzheimers disease, before plaques deposition, and that these changes are associated with emotional symptoms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/540486v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@fb19a7org.highwire.dtl.DTLVardef@151454borg.highwire.dtl.DTLVardef@9c7a12org.highwire.dtl.DTLVardef@112633e_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

neuroscience↗