5‐HT6R null mutatrion induces synaptic and cognitive defects

Abstract

Serotonin 6 receptor (5‐HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism underlying 5‐HT6R activity in the central nervous system (CNS) is not fully understood. In the present study, 5‐HT6R null mutant (5‐HT6R−/−) mice were found to exhibit cognitive deficiencies and abnormal anxiety levels. 5‐HT6R is considered to be specifically localized on the primary cilia. We found that the loss of 5‐HT6R affected the Sonic Hedgehog signaling pathway in the primary cilia. 5‐HT6R−/− mice showed remarkable alterations in neuronal morphology, including dendrite complexity and axon initial segment morphology. Neurons lacking 5‐HT6R exhibited increased neuronal excitability. Our findings highlight the complexity of 5‐HT6R functions in the primary ciliary and neuronal physiology, supporting the theory that this receptor modulates neuronal morphology and transmission, and contributes to cognitive deficits in a variety of human diseases, such as AD, schizophrenia, and ciliopathies.

Physical Exercise-Induced Astrocytic Neuroprotection and Cognitive Improvement Through Primary Cilia and Mitogen-Activated Protein Kinases Pathway in Rats With Chronic Cerebral Hypoperfusion

“…Studying astrocytic primary cilia will provide useful clues for intervention in reactive astrocytes to combat various neuropathologies such as brain injury and ischemia ( Sterpka and Chen, 2018 ). Primary cilia can be used as sensors for chemical and mechanical cues from cellular environment and play critical roles in transducing environmental stimuli and concentrating signal molecules to regulate cellular properties ( Sun et al, 2021 ; Tereshko et al, 2021 ). However, current research about the effects of physical exercise on primary cilia is still limited.…”

The role of ciliopathy-associated type 3 adenylyl cyclase in infanticidal behavior in virgin adult male mice

“…Similarly, a functional cilium in the CNS is crucial for maintaining the connectivity of neurons ( Bowie and Goetz, 2020 ; Guo et al., 2017 ; Haq et al., 2019 ; Kumamoto et al., 2012 ; Tereshko et al., 2021 ), which is highly dependent on ciliary AC3 signaling to tightly regulate the maintenance of the dendritic spine shape, size, and number in a dynamic manner ( Chen et al., 2016 ). Because neuronal circuitry integrity, as well as neuron maturation, sculpted by the dendritic spine and signaling of primary cilium via ciliary AC3 signaling in both the MOE and CNS ( Green et al., 2018 ; Guadiana et al., 2013 ; Guemez-Gamboa et al., 2014 ; Guo et al., 2019 ; Hildebrandt et al., 2011 ; Lee et al., 2020 ; Parisi, 2019 ; Reiter and Leroux, 2017 ; Sarkisian and Guadiana, 2015 ; Sun et al., 2021 ), is strongly associated with neurological and neurodevelopmental linked behaviors, including infanticidal behavior ( Amano et al., 2017 ; Autry et al., 2021 ; Gipson and Olive, 2017 ; Kohl, 2020 ; Kulkarni and Firestein, 2012 ; Mori and Sakano, 2021 ), it would appear reasonable to include them in a unitary model in which specialized ciliary AC3 signaling in the MOE, AON, or VMH is needed for maintenance of the infanticidal behaviors in adult virgin male mice, although the interpretation of the exact mechanism remains to be confirmed.…”

Dendritic Morphology Affects the Velocity and Amplitude of Back-propagating Action Potentials

“…Primary neurons were cultured from postnatal day 0 C57BL/6J mice following the rules and regulations of the Peking University Animal Care and Use Committee as described previously [24]. Fresh hippocampal tissue was dissected from the brain and digested with 0.25% trypsin (Gibco, NY, USA) for 15 min in an incubator at 37 °C, followed by inactivation with an equal volume of DMEM/ F12 medium (Gibco) with 10% fetal bovine serum (FBS) (Gibco).…”