Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 9 - 23
Опубликована: Июль 26, 2024
Язык: Английский
Nature Communications, Год журнала: 2025, Номер 16(1)
Опубликована: Янв. 2, 2025
Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) the nucleus accumbens (NAc), a central hub reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), brain-permeable small molecule FGF14R117, critical residue located within druggable pocket at FGF14/Nav1.6 PPI interface. We found modulates assembly and depolarizes voltage-dependence Nav1.6 inactivation with nanomolar potency by modulating intramolecular interaction between III-IV linker C-terminal domain channel. Consistent compound's effects on inactivation, enhances MSN ex vivo accumbal neuron firing rate murine models. Systemic administration maintains behavioral motivation preferentially during motivationally deficient conditions These were abrogated gene silencing Fgf14 NAc accompanied selective reduction dopamine levels consumption findings underscore to selectively regulate behaviors associated neuropsychiatric through targeting PPIs neurons. interfaces have emerged develop medications less side effects. Dvorak et al. show is an approach psychiatric discovery.
Язык: Английский
Процитировано
2
Cell, Год журнала: 2023, Номер 186(26), С. 5766 - 5783.e25
Опубликована: Дек. 1, 2023
The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that hominid-specific gene LRRC37B encodes a receptor expressed in cortical pyramidal (CPNs) selectively localized to axon initial segment (AIS), subcellular compartment triggering action potentials. Ectopic expression mouse CPNs vivo leads reduced intrinsic excitability, distinctive feature some classes CPNs. Molecularly, binds secreted ligand FGF13A voltage-gated sodium channel (Nav) β-subunit SCN1B. concentrates inhibitory effects on Nav function, thereby reducing specifically at AIS level. Electrophysiological recordings adult slices reveal lower neuronal excitability expressing LRRC37B. thus acts as species-specific modifier neuron linking genome cell evolution, with important implications for brain function diseases.
Язык: Английский
Процитировано
21
Journal of Biotechnology, Год журнала: 2024, Номер 389, С. 1 - 12
Опубликована: Май 1, 2024
Aging is associated with the slowdown of neuronal processing and cognitive performance in brain; however, exact cellular mechanisms behind this deterioration humans are poorly elucidated. Recordings human acute brain slices prepared from tissue resected during surgery enable investigation changes age. Although neocortical fast-spiking cells widely implicated network activities underlying processes, they vulnerable to neurodegeneration. Herein, we analyzed electrical properties 147 interneurons neocortex samples 106 patients aged 11–84 years. By studying electrophysiological features action potentials passive membrane properties, report that potential overshoot significantly decreases spike half-width increases Moreover, maximum-rise speed (but not repolarization or afterhyperpolarization amplitude) changed age, suggesting a particular weakening sodium channel current generated soma. Cell measured as input resistance, time constant, cell capacitance remained unaffected by senescence. Thus, conclude shows significant This may contribute cortical functions aging.
Язык: Английский
Процитировано
4
Advanced Science, Год журнала: 2024, Номер 11(33)
Опубликована: Июнь 27, 2024
Abstract Long‐range thalamocortical communication is central to anesthesia‐induced loss of consciousness and its reversal. However, isolating the specific neural networks connecting thalamic nuclei with various cortical regions for state‐specific anesthesia regulation challenging, biological underpinnings still largely unknown. Here, simultaneous electroencephalogram‐fuctional magnetic resonance imaging (EEG‐fMRI) deep brain stimulation are applied intralaminar thalamus in macaques under finely‐tuned propofol anesthesia. This approach led identification an intralaminar‐driven network responsible rapid arousal during slow‐wave oscillations. A network‐based RNA‐sequencing analysis conducted region‐, layer‐, cell‐specific gene expression data from independent transcriptomic atlases identifies 2489 genes preferentially expressed within this network, notably enriched potassium channels excitatory, parvalbumin‐expressing neurons, oligodendrocytes. Comparison human highlights conserved molecular cellular architectures that enable matching homologous genes, protein interactions, cell types across primates, providing novel insight into network‐focused transcriptional signatures arousal.
Язык: Английский
Процитировано
3
Science Advances, Год журнала: 2024, Номер 10(49)
Опубликована: Дек. 4, 2024
Artificial ion channels with controllable mono/monovalent cation separation fulfill important roles in biomedicine, separation, and energy conversion. However, it remains a daunting challenge to develop an artificial channel similar biological due ion-ion competitive transport lack of ion-gating ability channels. Here, we report conductive MXene membrane polydopamine-confined angstrom-scale propose voltage gating charge comediation strategy concurrently achieve gated selective separation. The shows highly switchable “on-off” ratio ∼9.9 for K + excellent /Li selectivity 40.9, outperforming the reported membranes electrical (typically 1.5 6). Theoretical simulations reveal that introduced high-charge cations such as Mg 2+ enable preferential distribution target over competing Li at entrance, surface potential reduces ionic barrier allowing pass quickly through channel.
Язык: Английский
Процитировано
3
Neurochemistry International, Год журнала: 2025, Номер unknown, С. 105990 - 105990
Опубликована: Май 1, 2025
Язык: Английский
Процитировано
0
Science Advances, Год журнала: 2023, Номер 9(41)
Опубликована: Окт. 12, 2023
Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances challenge input-output transfer functions of FSINs. Here, we test neurons from neurosurgery tissue, which mechanistic specializations FSINs explain their fast-signaling properties cortex. With morphological reconstructions, multipatch recordings, biophysical modeling, find threefold longer dendritic path, maintain between connected pyramidal through several mechanisms: stronger synapse strength excitatory inputs, dendrite diameter with reduced complexity, faster AP initiation, inhibitory output, while Na
Язык: Английский
Процитировано
8
Trends in Neurosciences, Год журнала: 2024, Номер 47(7), С. 491 - 505
Опубликована: Июнь 18, 2024
While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of neurobiological mechanisms that endow traits as well associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, molecular, morphological, functional features neural cell types, temporal differences development. Here, we summarize recent on their complex implications for study treatment diseases. We also consider key outstanding questions field discuss technologies foundational knowledge will be required to accelerate neurobiology.
Язык: Английский
Процитировано
2
STAR Protocols, Год журнала: 2024, Номер 5(4), С. 103313 - 103313
Опубликована: Сен. 17, 2024
Язык: Английский
Процитировано
2
Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Март 5, 2024
Abstract Synaptic mechanisms that contribute to memory consolidation in the human brain remain largely unexplored. The formation of lasting memories critically relies on sleep 1-3 . During slow wave sleep, neocortical neurons exhibit characteristic membrane potential oscillations known as UP and DOWN states 4-7 In this study, we show sleep-like modulate axonal action potentials temporarily enhance synaptic transmission between layer 2 & 3 pyramidal neurons. convergent microcircuit motifs, enhancement by synchronous leads efficient recruitment postsynaptic potentials, which turn results long-term stabilization strength. contrast, synapses undergo depression if presynaptic fail recruit potentials. Taken together, our study offers a mechanistic framework humans can explain how precise coupling neural activity waves gates plasticity, is substrate 8-12 This could inspire improved stimulation strategies targeting performance 13-18
Язык: Английский
Процитировано
1