COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex

2020 ◽  
Vol 30 (11) ◽  
pp. 5667-5685 ◽  
Author(s):  
Isabel Del Pino ◽  
Chiara Tocco ◽  
Elia Magrinelli ◽  
Andrea Marcantoni ◽  
Celeste Ferraguto ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Time Windows ◽  
Critical Time ◽  
Network Activity ◽  
Intrinsic Excitability ◽  
Developmental Sequence ◽  
Genetic Mechanisms ◽  
Layer V ◽  
Voltage Gated Ion Channels

Abstract The formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of S1 cortex specification. Altogether, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex.

scholarly journals COUP-TFI/Nr2f1 orchestrates intrinsic neuronal activity during cortical area patterning

2019 ◽  
Author(s):  
Isabel del Pino ◽  
Chiara Tocco ◽  
Elia Magrinelli ◽  
Andrea Marcantoni ◽  
Celeste Ferraguto ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Time Windows ◽  
Critical Time ◽  
Network Activity ◽  
Intrinsic Excitability ◽  
Genetic Mechanisms ◽  
Mapping Gene ◽  
Layer V ◽  
Voltage Gated Ion Channels

ABSTRACTThe formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for the area mapping gene Nr2f1 (also known as COUP-TFI), a key determinant of somatosensory area specification during development. We found that cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of somatosensory cortex specification. Together, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex.

scholarly journals BDNF Regulates the Intrinsic Excitability of Cortical Neurons

1999 ◽  
Vol 6 (3) ◽  
pp. 284-291
Author(s):  
Niraj S. Desai ◽  
Lana C. Rutherford ◽  
Gina G. Turrigiano
Keyword(s):  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Homeostatic Plasticity ◽  
Intrinsic Excitability ◽  
Intrinsic Properties ◽  
General Role ◽  
Outward Currents ◽  
Visual Cortical ◽  
Activity Dependent

Neocortical pyramidal neurons respond to prolonged activity blockade by modulating their balance of inward and outward currents to become more sensitive to synaptic input, possibly as a means of homeostatically regulating firing rates during periods of intense change in synapse number or strength. Here we show that this activity-dependent regulation of intrinsic excitability depends on the neurotrophin brain-derived neurotrophic factor (BDNF). In experiments on rat visual cortical cultures, we found that exogenous BDNF prevented, and a TrkB–IgG fusion protein reproduced, the change in pyramidal neuron excitability produced by activity blockade. Most of these effects were also observed in bipolar interneurons, indicating a very general role for BDNF in regulating neuronal excitability. Moreover, earlier work has demonstrated that BDNF mediates a different kind of homeostatic plasticity present in these same cultures: scaling of the quantal amplitude of AMPA-mediated synaptic inputs up or down as a function of activity. Taken together, these results suggest that BDNF may be the signal controlling a coordinated regulation of synaptic and intrinsic properties aimed at allowing cortical networks to adapt to long-lasting changes in activity.

Impaired Cl− Extrusion in Layer V Pyramidal Neurons of Chronically Injured Epileptogenic Neocortex

2005 ◽  
Vol 93 (4) ◽  
pp. 2117-2126 ◽  
Author(s):  
Xiaoming Jin ◽  
John R. Huguenard ◽  
David A. Prince
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Gabaergic Inhibition ◽  
Adult Rats ◽  
Positive Shift ◽  
Mature Brain ◽  
Significant Difference ◽  
The Difference ◽  
Layer V ◽  
Patch Technique

In the mature brain, the K+/Cl− cotransporter KCC2 is important in maintaining low [Cl−]i, resulting in hyperpolarizing GABA responses. Decreases in KCC2 after neuronal injuries result in increases in [Cl−]i and enhanced neuronal excitability due to depolarizing GABA responses. We used the gramicidin perforated-patch technique to measure ECl (∼ EGABA) in layer V pyramidal neurons in slices of partially isolated sensorimotor cortex of adult rats to explore the potential functional consequence of KCC2 downregulation in chronically injured cortex. EGABA was measured by recording currents evoked with brief GABA puffs at various membrane potentials. There was no significant difference in ECl between neurons in control and undercut animals (–71.2 ± 2.6 and –71.8 ± 2.8 mV, respectively). However, when loaded with Cl− by applying muscimol puffs at 0.2 Hz for 60 s, neurons in the undercut cortex had a significantly shorter time constant for the positive shift in ECl during the Cl− loading phase (4.3 ± 0.5 s for control and 2.2 ± 0.4 s for undercut, P < 0.01). The positive shift in ECl 3 s after the beginning of Cl− loading was also significantly larger in the undercut group than in the control, indicating that neurons in undercut cortex were less effective in maintaining low [Cl−]i during repetitive activation of GABAA receptors. Application of furosemide eliminated the difference between the control and undercut groups for both of these measures of [Cl−]i regulation. The results suggest an impairment in Cl− extrusion resulting from decreased KCC2 expression that may reduce the strength of GABAergic inhibition and contribute to epileptogenesis.

scholarly journals Slowly inactivating component of Na+ current in peri-somatic region of hippocampal CA1 pyramidal neurons

2013 ◽  
Vol 109 (5) ◽  
pp. 1378-1390 ◽  
Author(s):  
Yul Young Park ◽  
Daniel Johnston ◽  
Richard Gray
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Peak Amplitude ◽  
Neuronal Membrane ◽  
Inactivation Kinetics ◽  
Channel Blockers ◽  
Hippocampal Ca1 ◽  
Ramp Voltage ◽  
Dendritic Spikes ◽  
Voltage Gated Ion Channels

The properties of voltage-gated ion channels on the neuronal membrane shape electrical activity such as generation and backpropagation of action potentials, initiation of dendritic spikes, and integration of synaptic inputs. Subthreshold currents mediated by sodium channels are of interest because of their activation near rest, slow inactivation kinetics, and consequent effects on excitability. Modulation of these currents can also perturb physiological responses of a neuron that might underlie pathological states such as epilepsy. Using nucleated patches from the peri-somatic region of hippocampal CA1 neurons, we recorded a slowly inactivating component of the macroscopic Na+ current (which we have called INaS) that shared many biophysical properties with the persistent Na+ current, INaP, but showed distinctively faster inactivating kinetics. Ramp voltage commands with a velocity of 400 mV/s were found to elicit this component of Na+ current reliably. INaS also showed a more hyperpolarized I-V relationship and slower inactivation than those of the fast transient Na+ current ( INaT) recorded in the same patches. The peak amplitude of INaS was proportional to the peak amplitude of INaT but was much smaller in amplitude. Hexanol, riluzole, and ranolazine, known Na+ channel blockers, were tested to compare their effects on both INaS and INaT. The peak conductance of INaS was preferentially blocked by hexanol and riluzole, but the shift of half-inactivation voltage ( V1/2) was only observed in the presence of riluzole. Current-clamp measurements with hexanol suggested that INaS was involved in generation of an action potential and in upregulation of neuronal excitability.

scholarly journals An epitope specific patient-derived LGI1-autoantibody enhances neuronal excitability by modulating the Kv1.1 channel.

2021 ◽  
Author(s):  
Johanna Extrémet ◽  
Oussama El Far ◽  
Sarosh R Irani ◽  
Dominique Debanne ◽  
Michael Russier
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Channel Blocker ◽  
Intrinsic Excitability ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Specific Patient ◽  
Domain Specific ◽  
Ca3 Pyramidal Neurons ◽  
Induced Changes

Leucine-rich Glioma Inactivated protein 1 (LGI1) is expressed in the central nervous and genetic loss of function is associated with epileptic disorders. Also, patients with LGI1-directed autoantibodies have frequent focal seizures as a key feature of their disease. LGI1 is composed of a Leucine Rich Repeat (LRR) and an Epitempin (EPTP) domain. These domains are reported to interact with different aspects of the transsynaptic complex formed by LGI1 at excitatory synapses, including presynaptic Kv1 potassium channels. Patient-derived monoclonal antibodies (mAbs) are ideal reagents to study whether domain-specific LGI1-autoantibodies induce epileptiform activities in neurons, and their downstream mechanisms. To address this question, we measured the intrinsic excitability of CA3 pyramidal neurons in organotypic cultures from rat hippocampus treated with either a LRR- or an EPTP- reactive patient-derived mAb. The antibodies induced changes in neuronal intrinsic excitability which led us to measure their effects on Kv1-type potassium currents. We found an increase of intrinsic excitability correlated with a reduction of the sensitivity to a selective Kv1.1-channel blocker in neurons treated with the LRR mAb compared to the control, but not in neurons treated with the EPTP mAb. Our findings suggest LRR mAbs are able to modulate neuronal excitability that could account for epileptiform activities observed in patients.

Calcium-Activated Afterhyperpolarizations Regulate Synchronization and Timing of Epileptiform Bursts in Hippocampal CA3 Pyramidal Neurons

2006 ◽  
Vol 96 (6) ◽  
pp. 3028-3041 ◽  
Author(s):  
David Fernández de Sevilla ◽  
Julieta Garduño ◽  
Emilio Galván ◽  
Washington Buño
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Network Activity ◽  
Cellular Mechanisms ◽  
Burst Frequency ◽  
Potassium Conductances ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons

Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca2+-activated K+-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg2+-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO4 reduced burst frequency. Block of GABAA–B inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.

scholarly journals Chronic Cortical Injury and Epileptogensis: A Possible Role for Intracellular Chloride Homeostasis

2005 ◽  
Vol 5 (6) ◽  
pp. 239-240 ◽  
Author(s):  
F. Edward Dudek ◽  
Kevin J. Staley
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Adult Rats ◽  
Positive Shift ◽  
Chloride Homeostasis ◽  
Mature Brain ◽  
Significant Difference ◽  
The Difference ◽  
Layer V ◽  
Patch Technique

Impaired Cl– Extrusion in Layer V Pyramidal Neurons of Chronically Injured Epileptogenic Neocortex Jin X, Huguenard JR, Prince DA J Neurophysiol 2005;93:2117–2126 In the mature brain, the K+/Cl– cotransporter KCC2 is important in maintaining low [Cl–]i, resulting in hyperpolarizing GABA responses. Decreases in KCC2 after neuronal injuries result in increases in [Cl–]i and enhanced neuronal excitability due to depolarizing GABA responses. We used the gramicidin perforated-patch technique to measure ECl(∼ EGABA) in layer V pyramidal neurons in slices of partially isolated sensorimotor cortex of adult rats to explore the potential functional consequence of KCC2 downregulation in chronically injured cortex. EGABA was measured by recording currents evoked with brief GABA puffs at various membrane potentials. No significant difference was found in ECl between neurons in control and undercut animals (–71.2 ± 2.6 and −71.8 ± 2.8 mV, respectively). However, when loaded with Cl– by applying muscimol puffs at 0.2 Hz for 60 seconds, neurons in the undercut cortex had a significantly shorter time constant for the positive shift in ECl during the Cl– loading phase (4.3 ± 0.5 s for control and 2.2 ± 0.4 s for undercut; p < 0.01). The positive shift in ECl 3 seconds after the beginning of Cl– loading was also significantly larger in the undercut group than in the control, indicating that neurons in undercut cortex were less effective in maintaining low [Cl–]i during repetitive activation of GABAA receptors. Application of furosemide eliminated the difference between the control and undercut groups for both of these measures of [Cl–]i regulation. The results suggest an impairment in Cl– extrusion resulting from decreased KCC2 expression that may reduce the strength of GABAergic inhibition and contribute to epileptogenesis.

scholarly journals Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion

2021 ◽  
Author(s):  
Amber L Nolan ◽  
Vikaas S Sohal ◽  
Susanna Rosi
Keyword(s):  
Frontal Lobe ◽  
Pyramidal Neurons ◽  
Selective Vulnerability ◽  
Inhibitory Neurons ◽  
Intrinsic Excitability ◽  
Mental Flexibility ◽  
Neurologic Disability ◽  
Fast Spiking ◽  
Inhibitory Circuit ◽  
Layer V

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated if alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast spiking, somatostatin-expressing (SOM+) subtype of inhibitory neurons in layer V of the orbitofrontal cortex (OFC) two months after injury. These neurons exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons. By contrast, fast spiking, parvalbumin-expressing (PV+) interneurons did not show changes in intrinsic excitability or synaptic output. Impairments in SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.

scholarly journals Heterogeneous Firing Responses Predict Diverse Couplings to Presynaptic Activity in mice Layer V Pyramidal Neurons

2016 ◽  
Author(s):  
Yann Zerlaut ◽  
Alain Destexhe
Keyword(s):  
Membrane Potential ◽  
Synaptic Input ◽  
Pyramidal Neurons ◽  
Network Activity ◽  
Local Network ◽  
Potential Fluctuations ◽  
Branching Rule ◽  
Layer V ◽  
Different Levels ◽  
Membrane Potential Fluctuations

In this study, we present a theoretical framework combining experimental characterizations and analytical calculus to capture the firing rate input-output properties of single neurons in the fluctuation-driven regime. Our framework consists of a two-step procedure to treat independently how the dendritic input translates into somatic fluctuation variables, and how the latter determine action potential firing. We use this framework to investigate the functional impact of the heterogeneity in firing responses found experimentally in young mice layer V pyramidal cells. We first design and calibrate in vitro a simplified morphological model of layer V pyramidal neurons with a dendritic tree following Rall's branching rule. Then, we propose an analytical derivation for the membrane potential fluctuations at the soma as a function of the properties of the synaptic input in dendrites. This mathematical description allows us to easily emulate various forms of synaptic input: either balanced, unbalanced, synchronized, purely proximal or purely distal synaptic activity. We find that those different forms of input activity lead to various impact on the membrane potential fluctuations properties, thus raising the possibility that individual neurons will differentially couple to specific forms of activity as a result of their different firing response. We indeed found such a heterogeneous coupling between synaptic input and firing response for all types of presynaptic activity. This heterogeneity can be explained by different levels of cellular excitability in the case of the balanced, unbalanced, synchronized and purely distal activity. A notable exception appears for proximal dendritic inputs: increasing the input level can either promote firing response in some cells, or suppress it in some other cells whatever their individual excitability. This behavior can be explained by different sensitivities to the speed of the fluctuations, which was previously associated to different levels of sodium channel inactivation and density. Because local network connectivity rather targets proximal dendrites, our results suggest that this aspect of biophysical heterogeneity might be relevant to neocortical processing by controlling how individual neurons couple to local network activity.

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