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Acta Neuropathologica Communications Jul 2021Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50-70% of unknown origin. Recognized causes amount to 20-50% viral...
Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50-70% of unknown origin. Recognized causes amount to 20-50% viral infections. Approximately one third of affected subjects develops moderate and severe subsequent damage. Several neurotropic viruses can directly infect pyramidal neurons and induce neuronal death in cortex and hippocampus. The resulting encephalitic syndromes are frequently associated with cognitive deterioration and dementia, but involve numerous parallel and downstream cellular and molecular events that make the interpretation of direct consequences of sudden pyramidal neuronal loss difficult. This, however, would be pivotal for understanding how neuroinflammatory processes initiate the development of neurodegeneration, and thus for targeted prophylactic and therapeutic interventions. Here we utilized adult male NexCreERT2xRosa26-eGFP-DTA (= 'DTA') mice for the induction of a sterile encephalitis by diphtheria toxin-mediated ablation of cortical and hippocampal pyramidal neurons which also recruits immune cells into gray matter. We report multifaceted aftereffects of this defined process, including the expected pathology of classical hippocampal behaviors, evaluated in Morris water maze, but also of (pre)frontal circuit function, assessed by prepulse inhibition. Importantly, we modelled in encephalitis mice novel translationally relevant sequelae, namely altered social interaction/cognition, accompanied by compromised thermoreaction to social stimuli as convenient readout of parallel autonomic nervous system (dys)function. High resolution magnetic resonance imaging disclosed distinct abnormalities in brain dimensions, including cortical and hippocampal layering, as well as of cerebral blood flow and volume. Fluorescent tracer injection, immunohistochemistry and brain flow cytometry revealed persistent blood-brain-barrier perturbance and chronic brain inflammation. Surprisingly, blood flow cytometry showed no abnormalities in circulating major immune cell subsets and plasma high-mobility group box 1 (HMGB1) as proinflammatory marker remained unchanged. The present experimental work, analyzing multidimensional outcomes of direct pyramidal neuronal loss, will open new avenues for urgently needed encephalitis research.
Topics: Animals; Disease Models, Animal; Encephalitis; Gray Matter; Male; Mice; Mice, Inbred C57BL; Pyramidal Cells
PubMed: 34215338
DOI: 10.1186/s40478-021-01214-6 -
Nature Communications Mar 2023Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up...
Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood.
Topics: Hippocampus; Memory Disorders; Neurons; Pyramidal Cells; Seizures; Animals; Mice
PubMed: 36934089
DOI: 10.1038/s41467-023-37249-7 -
Cell Reports Feb 2016The dynamic interactions between synaptic excitation and inhibition (E/I) shape membrane potential fluctuations and determine patterns of neuronal outputs; however, the...
The dynamic interactions between synaptic excitation and inhibition (E/I) shape membrane potential fluctuations and determine patterns of neuronal outputs; however, the spatiotemporal organization of these interactions within a single cell is poorly understood. Here, we investigated the relationship between local synaptic excitation and global inhibition in hippocampal pyramidal neurons using functional dendrite imaging in combination with whole-cell recordings of inhibitory postsynaptic currents. We found that the sums of spine inputs over dendritic trees were counterbalanced by a proportional amount of somatic inhibitory inputs. This online E/I correlation was maintained in dendritic segments that were longer than 50 μm. However, at the single spine level, only 22% of the active spines were activated with inhibitory inputs. This inhibition-coupled activity occurred mainly in the spines with large heads. These results shed light on a microscopic E/I-balancing mechanism that operates at selected synapses and that may increase the accuracy of neural information.
Topics: Animals; Animals, Newborn; Dendritic Spines; Excitatory Postsynaptic Potentials; Hippocampus; Inhibitory Postsynaptic Potentials; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Wistar; Single-Cell Analysis; Synapses; Tissue Culture Techniques
PubMed: 26854220
DOI: 10.1016/j.celrep.2016.01.024 -
ENeuro May 2023haploinsufficiency in humans causes intellectual disability (ID). SYNGAP1 is highly expressed in cortical excitatory neurons and, reducing its expression in mice...
haploinsufficiency in humans causes intellectual disability (ID). SYNGAP1 is highly expressed in cortical excitatory neurons and, reducing its expression in mice accelerates the maturation of excitatory synapses during sensitive developmental periods, restricts the critical period window for plasticity, and impairs cognition. However, its specific role in interneurons remains largely undetermined. In this study, we investigated the effects of conditional disruption in medial ganglionic eminence (MGE)-derived interneurons on hippocampal interneuron firing properties and excitatory synaptic inputs, as well as on pyramidal cell synaptic inhibition and synaptic integration. We show that conditional disruption in MGE-derived interneurons results in cell-specific impairment of firing properties of hippocampal Nkx2.1 fast-spiking interneurons, with enhancement of their AMPA receptor (AMPAR)-mediated excitatory synaptic inputs but compromised short-term plasticity. In contrast, regular-spiking Nkx2.1 interneurons are largely unaffected. These changes are associated with impaired pyramidal cell synaptic inhibition and enhanced summation of excitatory responses. Unexpectedly, we found that the allele used in this study contains inverted loxP sites and that its targeted recombination in MGE-derived interneurons induces some cell loss during embryonic development and the reversible inversion of the sequence flanked by the loxP sites in postmitotic cells. Together, these results suggest that plays a role in cell-specific regulation of hippocampal interneuron function and inhibition of pyramidal cells in mice. However, because of our finding that the allele used in this study contains inverted loxP sites, it will be important to further investigate interneuron function using a different conditional allele.
Topics: Humans; Mice; Animals; Mice, Transgenic; Interneurons; Pyramidal Cells; Hippocampus; Recombination, Genetic; ras GTPase-Activating Proteins
PubMed: 37072176
DOI: 10.1523/ENEURO.0475-22.2023 -
Neuroscience Letters Nov 2020The hyperpolarizing activity of γ-aminobutyric acid A (GABA) receptors depends on the intracellular chloride gradient that is developmentally regulated by the activity...
BACKGROUND
The hyperpolarizing activity of γ-aminobutyric acid A (GABA) receptors depends on the intracellular chloride gradient that is developmentally regulated by the activity of the chloride extruder potassium (K) chloride (Cl) cotransporter 2 (KCC2). In humans and rodents, KCC2 expression can be detected at birth. In rodents, KCC2 expression progressively increases and reaches adult-like levels by the second postnatal week of life. Several studies report changes in KCC2 expression levels in response to early-life injuries. However, the functional contribution of KCC2 in maintaining the excitation-inhibition balance in the neonatal brain is not clear. In the current study, we examined the effect of KCC2 antagonism on the neonatal brain activity under hyperexcitable conditions ex vivo and in vivo.
METHODS
Ex vivo electrophysiology experiments were performed on hippocampal slices prepared from 7 to 9 days-old (P7-P9) male rats. Excitability of CA1 pyramidal neurons bathed in zero-Mg buffer was measured using single-unit extracellular (loose) or cell-attach protocol before and after application of VU0463271, a specific antagonist of KCC2. To examine the functional role of KCC2 in vivo, the effect of VU0463271 on hypoxia-ischemia (HI)-induced ictal (seizures and brief runs of epileptiform discharges - BREDs), and inter-ictal spike and sharp-wave activity was measured in P7 male rats. A highly sensitive LC-MS/MS method was used to determine the distribution and the concentration of VU0463271 in the brain.
RESULTS
Ex vivo blockade of KCC2 by VU0463271 significantly increased the frequency of zero-Mg-triggered spiking in CA1 pyramidal neurons. Similarly, in vivo administration of VU0463271 significantly increased the number of ictal events, BREDs duration, and spike and sharp-wave activity in HI rats. LC-MS/MS data revealed that following systemic administration, VU0463271 rapidly reached brain tissues and distributed well among different brain regions.
CONCLUSION
The results suggest that KCC2 plays a critical functional role in maintaining the balance of excitation-inhibition in the neonatal brain, and thus it can be used as a therapeutic target to ameliorate injury associated with hyperexcitability in newborns.
Topics: Action Potentials; Animals; Electroencephalography; Hippocampus; Male; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Seizures; Symporters; K Cl- Cotransporters
PubMed: 32860887
DOI: 10.1016/j.neulet.2020.135324 -
The Journal of Physiology Jun 2023Tinnitus affects roughly 15%-20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage...
Tinnitus affects roughly 15%-20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage to the auditory periphery, resulting in a cascade of maladaptive plastic changes at multiple levels of the central auditory neuraxis as well as limbic and non-auditory cortical centres. Using a well-established condition-suppression model of tinnitus, we measured tinnitus-related changes in the microcircuits of excitatory/inhibitory neurons onto layer 5 pyramidal neurons (PNs), as well as changes in the excitability of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1). Patch-clamp recordings from PNs in A1 slices showed tinnitus-related increases in spontaneous excitatory postsynaptic currents (sEPSCs) and decreases in spontaneous inhibitory postsynaptic currents (sIPSCs). Both measures could be correlated to the rat's behavioural evidence of tinnitus. Tinnitus-related changes in PN excitability were independent of changes in A1 excitatory or inhibitory cell numbers. VIP neurons, part of an A1 local circuit that can control the excitation of layer 5 PNs via disinhibitory mechanisms, showed significant tinnitus-related increases in excitability that directly correlated with the rat's behavioural tinnitus score. That PN and VIP changes directly correlated to tinnitus behaviour suggests an important role in A1 tinnitus pathology. Tinnitus-related A1 changes were similar to findings in studies of neuropathic pain in somatosensory cortex suggesting a common pathology of these troublesome perceptual impairments. Improved understanding between excitatory, inhibitory and disinhibitory sensory cortical circuits can serve as a model for testing therapeutic approaches to the treatment of tinnitus and chronic pain. KEY POINTS: We identified tinnitus-related changes in synaptic function of specific neuronal subtypes in a reliable animal model of tinnitus. The findings show direct and indirect tinnitus-related losses of normal inhibitory function at A1 layer 5 pyramidal cells, and increased VIP excitability. The findings are similar to what has been shown for neuropathic pain suggesting that restoring normal inhibitory function at synaptic inputs onto A1 pyramidal neurons (PNs) could conceptually reduce tinnitus discomfort.
Topics: Rats; Animals; Tinnitus; Vasoactive Intestinal Peptide; Auditory Cortex; Neurons; Pyramidal Cells
PubMed: 37119035
DOI: 10.1113/JP284675 -
ELife Oct 2020In vitro work revealed that excitatory synaptic inputs to hippocampal inhibitory interneurons could undergo Hebbian, associative, or non-associative plasticity. Both...
In vitro work revealed that excitatory synaptic inputs to hippocampal inhibitory interneurons could undergo Hebbian, associative, or non-associative plasticity. Both behavioral and learning-dependent reorganization of these connections has also been demonstrated by measuring spike transmission probabilities in pyramidal cell-interneuron spike cross-correlations that indicate monosynaptic connections. Here we investigated the activity-dependent modification of these connections during exploratory behavior in rats by optogenetically inhibiting pyramidal cell and interneuron subpopulations. Light application and associated firing alteration of pyramidal and interneuron populations led to lasting changes in pyramidal-interneuron connection weights as indicated by spike transmission changes. Spike transmission alterations were predicted by the light-mediated changes in the number of pre- and postsynaptic spike pairing events and by firing rate changes of interneurons but not pyramidal cells. This work demonstrates the presence of activity-dependent associative and non-associative reorganization of pyramidal-interneuron connections triggered by the optogenetic modification of the firing rate and spike synchrony of cells.
Topics: Animals; Exploratory Behavior; Hippocampus; Interneurons; Male; Optogenetics; Pyramidal Cells; Rats; Rats, Long-Evans
PubMed: 33016875
DOI: 10.7554/eLife.61106 -
Cell Reports Nov 2018Spatial navigation relies on visual landmarks as well as on self-motion information. In familiar environments, both place and grid cells maintain their firing fields in...
Spatial navigation relies on visual landmarks as well as on self-motion information. In familiar environments, both place and grid cells maintain their firing fields in darkness, suggesting that they continuously receive information about locomotion speed required for path integration. Consistently, "speed cells" have been previously identified in the hippocampal formation and characterized in detail in the medial entorhinal cortex. Here we investigated speed-correlated firing in the hippocampus. We show that CA1 has speed cells that are stable across contexts, position in space, and time. Moreover, their speed-correlated firing occurs within theta cycles, independently of theta frequency. Interestingly, a physiological classification of cell types reveals that all CA1 speed cells are inhibitory. In fact, while speed modulates pyramidal cell activity, only the firing rate of interneurons can accurately predict locomotion speed on a sub-second timescale. These findings shed light on network models of navigation.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Hippocampus; Interneurons; Male; Pyramidal Cells; Rats, Long-Evans; Theta Rhythm; Time Factors
PubMed: 30428354
DOI: 10.1016/j.celrep.2018.10.054 -
PloS One 2015Hippocampal pyramidal cells and dentate granule cells develop morphologically distinct dendritic arbors, yet also share some common features. Both cell types form a long...
Hippocampal pyramidal cells and dentate granule cells develop morphologically distinct dendritic arbors, yet also share some common features. Both cell types form a long apical dendrite which extends from the apex of the cell soma, while short basal dendrites are developed only in pyramidal cells. Using quantitative morphometric analyses of mouse hippocampal cultures, we evaluated the differences in dendritic arborization patterns between pyramidal and granule cells. Furthermore, we observed and described the final apical dendrite determination during dendritic polarization by time-lapse imaging. Pyramidal and granule cells in culture exhibited similar dendritic patterns with a single principal dendrite and several minor dendrites so that the cell types were not readily distinguished by appearance. While basal dendrites in granule cells are normally degraded by adulthood in vivo, cultured granule cells retained their minor dendrites. Asymmetric growth of a single principal dendrite harboring the Golgi was observed in both cell types soon after the onset of dendritic growth. Time-lapse imaging revealed that up until the second week in culture, final principal dendrite designation was not stabilized, but was frequently replaced by other minor dendrites. Before dendritic polarity was stabilized, the Golgi moved dynamically within the soma and was repeatedly repositioned at newly emerging principal dendrites. Our results suggest that polarized growth of the apical dendrite is regulated by cell intrinsic programs, while regression of basal dendrites requires cue(s) from the extracellular environment in the dentate gyrus. The apical dendrite designation is determined from among multiple growing dendrites of young developing neurons.
Topics: Animals; Cell Differentiation; Cells, Cultured; Dendrites; Dentate Gyrus; Glial Fibrillary Acidic Protein; Glutamate Decarboxylase; Golgi Apparatus; Hippocampus; Immunohistochemistry; Mice, Inbred ICR; Microscopy, Confocal; Nerve Tissue Proteins; Neurons; Primary Cell Culture; Pyramidal Cells; Time-Lapse Imaging
PubMed: 25705877
DOI: 10.1371/journal.pone.0118482 -
Cerebral Cortex (New York, N.Y. : 1991) Oct 2021Many investigators who make extracellular recordings from populations of cortical neurons are now using spike shape parameters, and particularly spike duration, as a...
Many investigators who make extracellular recordings from populations of cortical neurons are now using spike shape parameters, and particularly spike duration, as a means of classifying different neuronal sub-types. Because of the nature of the experimental approach, particularly that involving nonhuman primates, it is very difficult to validate directly which spike characteristics belong to particular types of pyramidal neurons and interneurons, as defined by modern histological approaches. This commentary looks at the way antidromic identification of pyramidal cells projecting to different targets, and in particular, pyramidal tract neurons (PTN), can inform the utility of spike width classification. Spike duration may provide clues to a diversity of function across the pyramidal cell population, and also highlights important differences that exist across species. Our studies suggest that further electrophysiological and optogenetic approaches are needed to validate spike duration as a means of cell classification and to relate this to well-established histological differences in neocortical cell types.
Topics: Action Potentials; Animals; Interneurons; Neurons; Pyramidal Cells; Pyramidal Tracts
PubMed: 34117760
DOI: 10.1093/cercor/bhab147