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.

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.

Excitatory and Inhibitory Postsynaptic Currents in a Rat Model of Epileptogenic Microgyria

2005 ◽  
Vol 93 (2) ◽  
pp. 687-696 ◽  
Author(s):  
K. M. Jacobs ◽  
D. A. Prince
Keyword(s):  
Rat Model ◽  
Pyramidal Neurons ◽  
Intractable Epilepsy ◽  
Pyramidal Cells ◽  
Excitatory Input ◽  
Inhibitory Neurons ◽  
Cell Group ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Layer V

Developmental cortical malformations are common in patients with intractable epilepsy; however, mechanisms contributing to this epileptogenesis are currently poorly understood. We previously characterized hyperexcitability in a rat model that mimics the histopathology of human 4-layered microgyria. Here we examined inhibitory and excitatory postsynaptic currents in this model to identify functional alterations that might contribute to epileptogenesis associated with microgyria. We recorded isolated whole cell excitatory postsynaptic currents and GABAA receptor-mediated inhibitory currents (EPSCs and IPSCs) from layer V pyramidal neurons in the region previously shown to be epileptogenic (paramicrogyral area) and in homotopic control cortex. Epileptiform-like activity could be evoked in 60% of paramicrogyral (PMG) cells by local stimulation. The peak conductance of both spontaneous and evoked IPSCs was significantly larger in all PMG cells compared with controls. This difference in amplitude was not present after blockade of ionotropic glutamatergic currents or for miniature (m)IPSCs, suggesting that it was due to the excitatory afferent activity driving inhibitory neurons. This conclusion was supported by the finding that glutamate receptor antagonist application resulted in a significantly greater reduction in spontaneous IPSC frequency in one PMG cell group (PMGE) compared with control cells. The frequency of both spontaneous and miniature EPSCs was significantly greater in all PMG cells, suggesting that pyramidal neurons adjacent to a microgyrus receive more excitatory input than do those in control cortex. These findings suggest that there is an increase in numbers of functional excitatory synapses on both interneurons and pyramidal cells in the PMG cortex perhaps due to hyperinnervation by cortical afferents originally destined for the microgyrus proper.

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.

Nicotinic activity depresses synaptic potentiation in layer V pyramidal neurons of mouse insular cortex

Neuroscience ◽  
2017 ◽  
Vol 358 ◽  
pp. 13-27 ◽  
Author(s):  
Hajime Sato ◽  
Tsutomu Kawano ◽  
Dong Xu Yin ◽  
Takafumi Kato ◽  
Hiroki Toyoda
Keyword(s):  
Pyramidal Neurons ◽  
Insular Cortex ◽  
Synaptic Potentiation ◽  
Layer V

Dendritic changes of the pyramidal neurons in layer V of sensory-motor cortex of the rat brain during the postresuscitation period

Resuscitation ◽  
1997 ◽  
Vol 35 (2) ◽  
pp. 157-164 ◽  
Author(s):  
Victor A Akulinin ◽  
Sergey S Stepanov ◽  
Valeriy V Semchenko ◽  
Pavel V Belichenko
Keyword(s):  
Motor Cortex ◽  
Rat Brain ◽  
Pyramidal Neurons ◽  
Postresuscitation Period ◽  
Sensory Motor ◽  
Layer V

scholarly journals Sex-dependent role for EPHB2 in brain development and autism-associated behavior

2021 ◽  
Author(s):  
Ahlem Assali ◽  
Jennifer Y. Cho ◽  
Evgeny Tsvetkov ◽  
Abha R. Gupta ◽  
Christopher W. Cowan
Keyword(s):  
Pyramidal Neurons ◽  
De Novo ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Mice ◽  
Sensory Sensitivity ◽  
Hyperactivity Disorder ◽  
Specific Effects ◽  
Layer V

AbstractAutism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

Stimulation of 5-HT2 Receptors in Prefrontal Pyramidal Neurons Inhibits Cav1.2 L-Type Ca2+Currents Via a PLCβ/IP3/Calcineurin Signaling Cascade

2002 ◽  
Vol 87 (5) ◽  
pp. 2490-2504 ◽  
Author(s):  
Michelle Day ◽  
Patricia A. Olson ◽  
Josef Platzer ◽  
Joerg Striessnig ◽  
D. James Surmeier
Keyword(s):  
Pyramidal Neurons ◽  
Inositol Trisphosphate ◽  
Cell Voltage ◽  
Signaling Cascade ◽  
Channel Modulation ◽  
Receptor Modulation ◽  
Bath Application ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Layer V

There is growing evidence linking alterations in serotonergic signaling in the prefrontal cortex to the etiology of schizophrenia. Prefrontal pyramidal neurons are richly innervated by serotonergic fibers and express high levels of serotonergic 5-HT2-class receptors. It is unclear, however, how activation of these receptors modulates cellular activity. To help fill this gap, whole cell voltage-clamp and single-cell RT-PCR studies of acutely isolated layer V–VI prefrontal pyramidal neurons were undertaken. The vast majority (>80%) of these neurons had detectable levels of 5-HT2A or 5-HT2C receptor mRNA. Bath application of 5-HT2 agonists inhibited voltage-dependent Ca2+ channel currents. L-type Ca2+ channels were a particularly prominent target of this signaling pathway. The L-type channel modulation was blocked by disruption of Gαq signaling or by inhibition of phospholipase Cβ. Antagonism of intracellular inositol trisphosphate signaling, chelation of intracellular Ca2+, or depletion of intracellular Ca2+ stores also blocked this modulation. Inhibition of the Ca2+-dependent phosphatase calcineurin prevented receptor-mediated modulation of L-type currents. Last, the 5-HT2 receptor modulation was robustly expressed in neurons from Cav1.3 knockout mice. These findings argue that 5-HT2receptors couple through Gαq proteins to trigger a phospholipase Cβ/inositol trisphosphate signaling cascade resulting in the mobilization of intracellular Ca2+, activation of calcineurin, and inhibition of Cav1.2 L-type Ca2+currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons.

scholarly journals Two Populations of Layer V Pyramidal Cells of the Mouse Neocortex: Development and Sensitivity to Anesthetics

2005 ◽  
Vol 94 (5) ◽  
pp. 3357-3367 ◽  
Author(s):  
Elodie Christophe ◽  
Nathalie Doerflinger ◽  
Daniel J. Lavery ◽  
Zoltán Molnár ◽  
Serge Charpak ◽  
...  
Keyword(s):  
Action Potential ◽  
Calcium Binding ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Subcortical Structures ◽  
Contralateral Cortex ◽  
Layer V ◽  
Intrinsic Membrane Properties ◽  
Two Populations

Previous studies have shown that layer V pyramidal neurons projecting either to subcortical structures or the contralateral cortex undergo different morphological and electrophysiological patterns of development during the first three postnatal weeks. To isolate the determinants of this differential maturation, we analyzed the gene expression and intrinsic membrane properties of layer V pyramidal neurons projecting either to the superior colliculus (SC cells) or the contralateral cortex (CC cells) by combining whole cell recordings and single-cell RT-PCR in acute slices prepared from postnatal day (P) 5–7 or P21–30 old mice. Among the 24 genes tested, the calcium channel subunits α1B and α1C, the protease Nexin 1, and the calcium-binding protein calbindin were differentially expressed in adult SC and CC cells and the potassium channel subunit Kv4.3 was expressed preferentially in CC cells at both stages of development. Intrinsic membrane properties, including input resistance, amplitude of the hyperpolarization-activated current, and action potential threshold, differed quantitatively between the two populations as early as from the first postnatal week and persisted throughout adulthood. However, the two cell types had similar regular action potential firing behaviors at all developmental stages. Surprisingly, when we increased the duration of anesthesia with ketamine–xylazine or pentobarbital before decapitation, a proportion of mature SC cells, but not CC cells, fired bursts of action potentials. Together these results indicate that the two populations of layer V pyramidal neurons already start to differ during the first postnatal week and exhibit different firing capabilities after anesthesia.

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