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Acta Pharmacologica Sinica Jun 2024Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of...
Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca influx evoked by high K solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.
PubMed: 38862816
DOI: 10.1038/s41401-024-01275-y -
The European Journal of Neuroscience Jun 2024The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum...
The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum radiatum (SR) receives input from the hippocampal CA3 region while the distal part in the stratum-lacunosum-moleculare (SLM) receives input mainly from the entorhinal cortex. The AMPA receptor-mediated (AMPA) signalling of SLM synapses in slices from neonatal rats was previously found to considerably differ from that of the SR synapses. In the present study, AMPA signalling of SLM synapses in 1-month-old rats has been examined, that is, when the hippocampus is essentially functionally mature. For the SR synapses, this time is characterized by a facilitatory shift in short-term plasticity, in the disappearance of labile postsynaptic AMPA signalling, a property thought to be important for early activity-dependent organization of neural circuits, and the expression of an adult form of long-term potentiation. We found that the SLM synapses alter their short-term plasticity similarly to that of the SR synapses. However, the labile postsynaptic AMPA signalling was not only maintained but substantially enhanced in the SLM synapses. The long-term potentiation observed was not of the adult form but like that of the neonatal SR synapses based on unsilencing of AMPA labile synapses. We propose that these features of the SLM synapses in the mature hippocampus will help to produce a flexible map of the multimodal sensory input reaching the SLM required for its conjunctive operation with the SR input to generate a proper functional output from the CA1 region.
PubMed: 38857895
DOI: 10.1111/ejn.16440 -
Development (Cambridge, England) Jul 2024The function of medial entorhinal cortex layer II (MECII) excitatory neurons has been recently explored. MECII dysfunction underlies deficits in spatial navigation and...
The function of medial entorhinal cortex layer II (MECII) excitatory neurons has been recently explored. MECII dysfunction underlies deficits in spatial navigation and working memory. MECII neurons comprise two major excitatory neuronal populations, pyramidal island and stellate ocean cells, in addition to the inhibitory interneurons. Ocean cells express reelin and surround clusters of island cells that lack reelin expression. The influence of reelin expression by ocean cells and interneurons on their own morphological differentiation and that of MECII island cells has remained unknown. To address this, we used a conditional reelin knockout (RelncKO) mouse to induce reelin deficiency postnatally in vitro and in vivo. Reelin deficiency caused dendritic hypertrophy of ocean cells, interneurons and only proximal dendritic compartments of island cells. Ca2+ recording showed that both cell types exhibited an elevation of calcium frequencies in RelncKO, indicating that the hypertrophic effect is related to excessive Ca2+ signalling. Moreover, pharmacological receptor blockade in RelncKO mouse revealed malfunctioning of GABAB, NMDA and AMPA receptors. Collectively, this study emphasizes the significance of reelin in neuronal growth, and its absence results in dendrite hypertrophy of MECII neurons.
Topics: Reelin Protein; Animals; Entorhinal Cortex; Dendrites; Cell Adhesion Molecules, Neuronal; Serine Endopeptidases; Nerve Tissue Proteins; Extracellular Matrix Proteins; Mice, Knockout; Mice; Interneurons; Neurons; Calcium Signaling
PubMed: 38856043
DOI: 10.1242/dev.202449 -
Philosophical Transactions of the Royal... Jul 2024Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational... (Review)
Review
Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons with a specific focus on the latest developments from studies. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Pyramidal Cells; Neuronal Plasticity; Animals; Brain; Long-Term Potentiation; Synapses; Humans
PubMed: 38853566
DOI: 10.1098/rstb.2023.0231 -
Philosophical Transactions of the Royal... Jul 2024Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to...
Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Nitric Oxide; Animals; Cerebral Cortex; Presynaptic Terminals; Receptors, Kainic Acid; Patch-Clamp Techniques; Rats; Pyramidal Cells; Nitric Oxide Synthase; Mice
PubMed: 38853563
DOI: 10.1098/rstb.2023.0475 -
Philosophical Transactions of the Royal... Jul 2024Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand...
Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand better the possible impact of either LTP form, we explored a realistic model of a CA1 pyramidal cell equipped with known membrane mechanisms and multiple, stochastic excitatory axo-spinous synapses. Our simulations were designed to establish an input-output transfer function, the dependence between the frequency of presynaptic action potentials triggering probabilistic synaptic discharges and the average frequency of postsynaptic spiking. We found that, within the typical physiological range, potentiation of the postsynaptic current results in a greater overall output than an equivalent increase in presynaptic release probability. This difference grows stronger at lower input frequencies and lower release probabilities. Simulations with a non-hierarchical circular network of principal neurons indicated that equal increases in either synaptic fidelity or synaptic strength of individual connections also produce distinct changes in network activity, although the network phenomenology is likely to be complex. These observations should help to interpret the machinery of LTP phenomena documented . This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Models, Neurological; Synapses; Pyramidal Cells; Animals; Computer Simulation; Action Potentials; CA1 Region, Hippocampal
PubMed: 38853561
DOI: 10.1098/rstb.2023.0235 -
Philosophical Transactions of the Royal... Jul 2024-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic...
-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic NMDAR (pre-NMDAR) function is largely unexplored. Different pre-NMDAR subunit populations are documented at synapses, suggesting that subunit composition influences neuronal transmission. Here, we used electrophysiological recordings at Schaffer collateral-CA1 synapses partnered with Ca imaging and glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of pre-NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential-evoked Ca influx via modulation of small-conductance Ca-activated K+ channels, while activation of the GluN2A population does the opposite. Critically, the level of functional expression of the subunits is subject to homeostatic regulation, bidirectionally affecting short-term facilitation, thus providing a capacity for a fine adjustment of information transfer. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Receptors, N-Methyl-D-Aspartate; Animals; Small-Conductance Calcium-Activated Potassium Channels; Action Potentials; Calcium; Rats; Synapses; Neuronal Plasticity; Pyramidal Cells
PubMed: 38853550
DOI: 10.1098/rstb.2023.0222 -
Neurobiology of Disease Aug 2024Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the...
Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flna mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.
Topics: Animals; Filamins; rac1 GTP-Binding Protein; Mice; Cerebral Cortex; Actin Depolymerizing Factors; Pyramidal Cells; Neurogenesis; GTPase-Activating Proteins; Neurons; Mice, Transgenic; Periventricular Nodular Heterotopia; Neuropeptides
PubMed: 38852754
DOI: 10.1016/j.nbd.2024.106558 -
Journal of Neurology, Neurosurgery, and... Jun 2024Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have...
BACKGROUND
Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS).
METHODS
We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AI) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients.
RESULTS
MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AI correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01).
CONCLUSIONS
Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.
PubMed: 38844341
DOI: 10.1136/jnnp-2024-333554 -
Science (New York, N.Y.) Jun 2024In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay...
In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.
Topics: Animals; Male; Mice; Analgesics, Opioid; Connectome; Mice, Inbred C57BL; Neurons; Opioid-Related Disorders; Oxycodone; Parabrachial Nucleus; Prefrontal Cortex; Pyramidal Cells; Receptors, Opioid, mu; Reward; Substance Withdrawal Syndrome; Transcriptome; Avoidance Learning
PubMed: 38843332
DOI: 10.1126/science.adn0886