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The Journal of Neuroscience : the... Nov 2015The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K(+) current in many...
UNLABELLED
The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K(+) current in many mammalian central neurons. Kv2.1 exhibits robust expression across many neuron types and is unique in its conditional role in modulating intrinsic excitability through changes in its phosphorylation state, which affect Kv2.1 expression, localization, and function. Much less is known of the highly related Kv2.2 subunit, especially in forebrain neurons. Here, through combined use of cortical layer markers and transgenic mouse lines, we show that Kv2.1 and Kv2.2 are localized to functionally distinct cortical cell types. Kv2.1 expression is consistently high throughout all cortical layers, especially in layer (L) 5b pyramidal neurons, whereas Kv2.2 expression is primarily limited to neurons in L2 and L5a. In addition, L4 of primary somatosensory cortex is strikingly devoid of Kv2.2 immunolabeling. The restricted pattern of Kv2.2 expression persists in Kv2.1-KO mice, suggesting distinct cell- and layer-specific functions for these two highly related Kv2 subunits. Analyses of endogenous Kv2.2 in cortical neurons in situ and recombinant Kv2.2 expressed in heterologous cells reveal that Kv2.2 is largely refractory to stimuli that trigger robust, phosphorylation-dependent changes in Kv2.1 clustering and function. Immunocytochemistry and voltage-clamp recordings from outside-out macropatches reveal distinct cellular expression patterns for Kv2.1 and Kv2.2 in intratelencephalic and pyramidal tract neurons of L5, indicating circuit-specific requirements for these Kv2 paralogs. Together, these results support distinct roles for these two Kv2 channel family members in mammalian cortex.
SIGNIFICANCE STATEMENT
Neurons within the neocortex are arranged in a laminar architecture and contribute to the input, processing, and/or output of sensory and motor signals in a cell- and layer-specific manner. Neurons of different cortical layers express diverse populations of ion channels and possess distinct intrinsic membrane properties. Here, we show that the Kv2 family members Kv2.1 and Kv2.2 are expressed in distinct cortical layers and pyramidal cell types associated with specific corticostriatal pathways. We find that Kv2.1 and Kv2.2 exhibit distinct responses to acute phosphorylation-dependent regulation in brain neurons in situ and in heterologous cells in vitro. These results identify a molecular mechanism that contributes to heterogeneity in cortical neuron ion channel function and regulation.
Topics: Animals; Cells, Cultured; Gene Expression Regulation; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Neocortex; Neurons; Organ Culture Techniques; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Shab Potassium Channels
PubMed: 26538660
DOI: 10.1523/JNEUROSCI.1897-15.2015 -
Hippocampus Apr 2019Recurrent excitatory synapses have theoretically been shown to play roles in memory storage and associative learning and are well described to occur in the CA3 region of...
Recurrent excitatory synapses have theoretically been shown to play roles in memory storage and associative learning and are well described to occur in the CA3 region of the hippocampus. Here, we report that the CA2 region also contains recurrent excitatory monosynaptic couplings. Using dual whole-cell patch-clamp recordings from CA2 pyramidal cells in mouse hippocampal slices under differential interference contrast microscopic controls, we evaluated monosynaptic excitatory connections. Unitary excitatory postsynaptic potentials occurred in 1.4% of 502 cell pairs. These connected pairs were preferentially located in the superficial layer and proximal part (CA2b) of the CA2 region. These results indicate that recurrent excitatory circuits are denser in the CA2 region than in the CA1 region, as well as in the CA3 region.
Topics: Animals; CA2 Region, Hippocampal; Excitatory Postsynaptic Potentials; Mice; Organ Culture Techniques; Pyramidal Cells; Synapses
PubMed: 30588702
DOI: 10.1002/hipo.23064 -
Hippocampus May 2016Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells...
Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells undergo mossy fiber sprouting in the dentate gyrus which contributes to a recurrent, proepileptogenic circuitry in the hippocampus. Here it is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions. Using the intrahippocampal kainate mouse model for MTLE and the CA2-specific markers Purkinje cell protein 4 (PCP4) and regulator of G-Protein signaling 14 (RGS14), it was found that during epileptogenesis CA2 neurons survive and disperse in direction of CA3 and CA1 resulting in a significantly elongated CA2 region. Using transgenic mice that express enhanced green fluorescent protein (eGFP) in granule cells and mossy fibers, we show that the recently described mossy fiber projection to CA2 undergoes sprouting resulting in aberrant large, synaptoporin-expressing mossy fiber boutons which surround the CA2 pyramidal cell somata. This opens up the potential for altered synaptic transmission that might contribute to epileptic activity in CA2. Indeed, intrahippocampal recordings in freely moving mice revealed that epileptic activity occurs concomitantly in the dentate gyrus and in CA2. Altogether, the results call attention to CA2 as a region affected by MTLE-associated pathological restructuring.
Topics: Animals; CA2 Region, Hippocampal; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Fluoresceins; Functional Laterality; Green Fluorescent Proteins; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mossy Fibers, Hippocampal; Nerve Tissue Proteins; Pyramidal Cells; RGS Proteins; Synaptophysin; Time Factors
PubMed: 26482541
DOI: 10.1002/hipo.22543 -
Journal of Psychiatric Research Nov 2023Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was...
Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was to evaluate, at a cellular level, the size of both cell body and nucleus of pyramidal neurons located throughout the Cornu Ammonis (CA1 to CA4 regions). To perform this duty, we used 16 rats that were randomized into two groups: control and dietary lithium-treated. After one month, they were sacrificed and their brains removed for histopathological analysis. Serial photos of the entire Cornu Ammonis were taken and, after dividing them into 4 regions of interest, we measured the cell body and nucleus on each pyramidal neuron belonging to the first 5 photos of each region of interest. As a result of this histological analysis, cell body area and nuclear area were significantly larger in the experimental group in a specific area of the Cornu Ammonis that could correspond to CA2 or the transition between CA1 and CA2. These results suggest that the effect of lithium is not homogeneous throughout the hippocampus and allows directing future studies to a specific area of this structure.
Topics: Animals; Pyramidal Cells; Rats; Male; Disease Models, Animal; Hippocampus; Rats, Wistar; Antimanic Agents; CA1 Region, Hippocampal
PubMed: 37826875
DOI: 10.1016/j.jpsychires.2023.10.001 -
Philosophical Transactions of the Royal... Mar 2017We compare the circuit and cellular mechanisms for homeostatic plasticity that have been discovered in rodent somatosensory (S1) and visual (V1) cortex. Both areas use... (Review)
Review
We compare the circuit and cellular mechanisms for homeostatic plasticity that have been discovered in rodent somatosensory (S1) and visual (V1) cortex. Both areas use similar mechanisms to restore mean firing rate after sensory deprivation. Two time scales of homeostasis are evident, with distinct mechanisms. Slow homeostasis occurs over several days, and is mediated by homeostatic synaptic scaling in excitatory networks and, in some cases, homeostatic adjustment of pyramidal cell intrinsic excitability. Fast homeostasis occurs within less than 1 day, and is mediated by rapid disinhibition, implemented by activity-dependent plasticity in parvalbumin interneuron circuits. These processes interact with Hebbian synaptic plasticity to maintain cortical firing rates during learned adjustments in sensory representations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.
Topics: Animals; Homeostasis; Mice; Neuronal Plasticity; Pyramidal Cells; Rats; Sensory Deprivation; Somatosensory Cortex; Visual Cortex
PubMed: 28093551
DOI: 10.1098/rstb.2016.0157 -
ELife Oct 2019The active properties of dendrites can support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views...
The active properties of dendrites can support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence and selectivity of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large learning capacity in individual neurons.
Topics: Animals; Calcium Signaling; Decision Making; Mice; Microscopy; Motor Cortex; Nerve Net; Pyramidal Cells; Touch Perception; Vibrissae
PubMed: 31663507
DOI: 10.7554/eLife.46966 -
Nature Mar 2021In 1986, electron microscopy was used to reconstruct by hand the entire nervous system of a roundworm, the nematode Caenorhabditis elegans. Since this landmark study,...
In 1986, electron microscopy was used to reconstruct by hand the entire nervous system of a roundworm, the nematode Caenorhabditis elegans. Since this landmark study, high-throughput electron-microscopic techniques have enabled reconstructions of much larger mammalian brain circuits at synaptic resolution. Nevertheless, it remains unknown how the structure of a synapse relates to its physiological transmission strength-a key limitation for inferring brain function from neuronal wiring diagrams. Here we combine slice electrophysiology of synaptically connected pyramidal neurons in the mouse somatosensory cortex with correlated light microscopy and high-resolution electron microscopy of all putative synaptic contacts between the recorded neurons. We find a linear relationship between synapse size and strength, providing the missing link in assigning physiological weights to synapses reconstructed from electron microscopy. Quantal analysis also reveals that synapses contain at least 2.7 neurotransmitter-release sites on average. This challenges existing release models and provides further evidence that neocortical synapses operate with multivesicular release, suggesting that they are more complex computational devices than thought, and therefore expanding the computational power of the canonical cortical microcircuitry.
Topics: Animals; Cell Size; Electrophysiological Phenomena; Male; Mice; Microscopy; Microscopy, Electron; Neocortex; Neurotransmitter Agents; Pyramidal Cells; Somatosensory Cortex; Synapses; Synaptic Transmission
PubMed: 33442056
DOI: 10.1038/s41586-020-03134-2 -
Neuron May 2022Cortical pyramidal neurons receive thousands of synaptic inputs and transform these into action potential output. In this issue of Neuron, Lafourcade et al. (2022)...
Cortical pyramidal neurons receive thousands of synaptic inputs and transform these into action potential output. In this issue of Neuron, Lafourcade et al. (2022) demonstrate that distinct long-range projections to retrosplenial cortex pyramidal neurons are coupled to diverse modes of dendritic integration.
Topics: Action Potentials; Axons; Dendrites; Neurons; Pyramidal Cells
PubMed: 35512635
DOI: 10.1016/j.neuron.2022.04.014 -
Nature Communications Jan 2021Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to...
Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to play a major role in drug addiction. However, cortical pyramidal projection neurons can be subdivided into two major types (intratelencephalic (IT) and pyramidal tract (PT)), with distinct inputs and projection targets, molecular and receptor profiles, morphologies and electrophysiological properties. Yet, how each of these cell populations modulate behavior related to addiction is unknown. We demonstrate that PT neurons regulate the positive features of a drug experience whereas IT neurons regulate the negative features. These findings support a revised theory of cortical function in addiction, with distinct cells and circuits mediating reward and aversion.
Topics: Animals; Cerebral Cortex; Cocaine; Electrophysiological Phenomena; Male; Pharmaceutical Preparations; Pyramidal Cells; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; Reward
PubMed: 33420090
DOI: 10.1038/s41467-020-20526-0 -
PLoS Computational Biology Sep 2022Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are...
Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation. We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal part of the apical dendrite and Ih-inhibiting modulation at the distal part of the apical dendrite can increase the layer V pyramidal excitability more than either of the two alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.
Topics: Action Potentials; Calcium; Cyclic Nucleotide-Gated Cation Channels; Dendrites; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Nucleotides, Cyclic; Pyramidal Cells
PubMed: 36099307
DOI: 10.1371/journal.pcbi.1010506