Accumulating evidence suggests a widespread role of serotonin 5-HT receptors (5-HTRs) in the physiology of cognitive and affective processing. However, we still lack insights into 5-HTR electrophysiology. Studies analyzing the 5-HTR-mediated changes in CA1 pyramidal neuron activity revealed that 5-HTR activation leads to the opening of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs). However, our group and others have shown that CA1 pyramidal cells increase their excitability following 5-HTR activation, an effect which cannot be explained by HCN channel opening. This suggests a different ionic mechanism might be responsible. To investigate this, we performed whole-cell patch clamp recordings of CA1 pyramidal cells in rat brain slices. It was found that acute 5-HTR activation increased membrane excitability and decreased spiking latency. Both effects were blocked by a selective 5-HTR antagonist. Spike latency in CA1 pyramidal cells is known to be regulated by transient outward voltage-dependent A-type potassium channels. Subsequent voltage clamp recordings revealed that acute 5-HTR activation inhibited A-type potassium currents. Pharmacological block of Kv4.2/4.3 potassium channel subunits prevented the 5-HTR agonist-induced changes in excitability and spiking latency, whereas blocking HCN channels had no influence on these effects. Taken together, the results reveal an ionic mechanism previously not known to be associated with 5-HTR activation. Inhibition of A-type potassium channels can fully account for increased CA1 pyramidal cell excitability after 5-HTR activation. These results can help explain a number of behavioral and physiological findings and will hopefully lead to a better understanding of 5-HT receptor signaling in health and disease.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108248 | DOI Listing |
Elife
January 2025
Department of Neurology, Baylor College of Medicine, Houston, United States.
variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path.
View Article and Find Full Text PDFJ Neurosci
January 2025
Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH 43210
Pyramidal cells (PCs) in CA1 hippocampus can be classified by their radial position as deep or superficial and organize into subtype-specific circuits necessary for differential information processing. Specifically, superficial PCs receive fewer inhibitory synapses from parvalbumin (PV)-expressing interneurons than deep PCs, resulting in weaker feedforward inhibition of input from CA3 Schaffer collaterals. Using mice, we investigated mechanisms underlying CA1 PC differentiation and the development of this inhibitory circuit motif.
View Article and Find Full Text PDFChin J Traumatol
December 2024
Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Department of Orthopedics, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China. Electronic address:
Purpose: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss.
Methods: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method.
J Cell Biol
February 2025
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Endocytosis, required for the uptake of receptors and their ligands, can also introduce pathological aggregates such as α-synuclein (α-syn) in Parkinson's Disease. We show here the unexpected presence of intrinsically perforated endolysosomes in neurons, suggesting involvement in the genesis of toxic α-syn aggregates induced by internalized preformed fibrils (PFFs). Aggregation of endogenous α-syn in late endosomes and lysosomes of human iPSC-derived neurons (iNs), seeded by internalized α-syn PFFs, caused the death of the iNs but not of the parental iPSCs and non-neuronal cells.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Introduction: Limited research has extensively analyzed neurodegenerative disease-related protein deposition patterns in the hippocampus.
Methods: This study examined the distribution of proteins in hippocampal subregions across major neurodegenerative diseases and explored their relation to each other. The area density of phosphorylated tau (p-tau), amyloid beta (Aβ), α-synuclein, and phosphorylated TDP-43 protein deposits together with pyramidal cell density in each hippocampal subregion, including CA1-4, prosubiculum (ProS), and subiculum was assessed in 166 cases encompassing various neurodegenerative diseases.
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