scholarly journals Pharmacological modulation of the voltage-gated neuronal Kv7/KCNQ/M-channel alters the intrinsic excitability and synaptic responses of pyramidal neurons in rat prefrontal cortex slices

2017 ◽  
Vol 38 (9) ◽  
pp. 1248-1256 ◽  
Author(s):  
Hui Peng ◽  
Xi-ling Bian ◽  
Fu-cui Ma ◽  
Ke-Wei Wang
Keyword(s):  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Intrinsic Excitability ◽  
Voltage Gated ◽  
Pharmacological Modulation ◽  
Cortex Slices ◽  
Synaptic Responses

scholarly journals Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Nawshaba Nawreen ◽  
Mark L. Baccei ◽  
James P. Herman
Keyword(s):  
Prefrontal Cortex ◽  
Traumatic Stress ◽  
Pyramidal Neurons ◽  
Male Rats ◽  
Intrinsic Excitability ◽  
Repetitive Firing ◽  
Membrane Excitability ◽  
Single Prolonged Stress ◽  
Prolonged Stress ◽  
Synaptic Drive

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed 1 week of recovery, following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.

scholarly journals Triumeq Increases Excitability of Pyramidal Neurons in the Medial Prefrontal Cortex by Facilitating Voltage-Gated Ca2+ Channel Function

2021 ◽  
Vol 11 ◽  
Author(s):  
Lihua Chen ◽  
Lena Al-Harthi ◽  
Xiu-Ti Hu
Keyword(s):  
Prefrontal Cortex ◽  
Side Effects ◽  
Medial Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Voltage Gated ◽  
Hiv Aids

Combination antiretroviral therapy (cART) suppresses HIV-1 replication, improves immune function, and prolongs the life of people living with HIV (PLWH). However, cART also induces neurotoxicity that could complicate HIV-induced neurodegeneration while reduce its therapeutic efficacy in treating HIV/AIDS. Triumeq is a first-line cART regimen, which is co-formulated by three antiretroviral drugs (ARVs), lamivudine (3TC), abcavir (ABC), and dolutegravir (DTG). Little is known about potential side effects of ARVs on the brain (including those co-formulating Triumeq), and their mechanisms impacting neuronal activity. We assessed acute (in vitro) and chronic (in vivo) effects of Triumeq and co-formulating ARVs on pyramidal neurons in rat brain slices containing the medial prefrontal cortex (mPFC) using patch-clamp recording approaches. We found that acute Triumeq or 3TC in vitro significantly increased firing of mPFC neurons in a concentration- and time-dependent manner. This neuronal hyperactivity was associated with enhanced Ca2+ influx through voltage-gated Ca2+ channels (VGCCs). Additionally, chronic treatment with Triumeq in vivo for 4 weeks (4 wks) also significantly increased firing and Ca2+ influx via VGCCs in mPFC neurons, which was not shown after 2 wks treatment. Such mPFC neuronal hyperexcitability was not found after 4 weeks treatments of individual ARVs. Further, chronic Triumeq exposure in vivo significantly enhanced mRNA expression of low voltage-activated (LVA) L-type Ca2+ channels (Cav1.3 L-channels), while changes in high voltage-activated (HVA) Cav1.2 L-channels were not observed. Collectively, these novel findings demonstrate that chronic cART induces hyperexcitability of mPFC pyramidal neurons by abnormally promoting VGCC overactivation/overexpression of VGCCs (including, but may not limited to, LVA-Cav1.3 L-channels), which could complicate HIV-induced neurotoxicity, and ultimately may contribute to HIV-associated neurocognitive disorders (HAND) in PLWH. Determining additional target(s) of cART in mPFC pyramidal neurons may help to improve the therapeutic strategies by minimizing the side effects of cART for treating HIV/AIDS.

scholarly journals Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex

2014 ◽  
Vol 111 (10) ◽  
pp. 1960-1972 ◽  
Author(s):  
Hannah J. Seong ◽  
Rudy Behnia ◽  
Adam G. Carter
Keyword(s):  
Prefrontal Cortex ◽  
Membrane Potential ◽  
Nmda Receptors ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
K Channels ◽  
Two Photon ◽  
Synaptic Potentials ◽  
Ampa And Nmda Receptors ◽  
Synaptic Responses

Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels.

Reduced Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Neurons in the Medial Prefrontal Cortex in a Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Xiao-Qin Zhang ◽  
Le Xu ◽  
Si-Yu Yang ◽  
Lin-Bo Hu ◽  
Fei-Yuan Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Intrinsic Excitability ◽  
Rodent Models ◽  
Morphological Complexity ◽  
Sholl Analysis ◽  
Model Of Alzheimer’S Disease

Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

scholarly journals Anesthesia and Surgery Induce a Functional Decrease Selectively in Excitatory Synaptic Transmission in Mouse Prefrontal Cortex Neurons

2020 ◽  
Author(s):  
Yu Matsumoto ◽  
Yuji Fujino ◽  
Hidemasa Furue
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Transmission ◽  
Cognitive Processes ◽  
Postoperative Delirium ◽  
Pyramidal Neurons ◽  
Functional Changes ◽  
Whole Cell Patch Clamp ◽  
Glutamate Receptor Antagonists ◽  
Plastic Change ◽  
Synaptic Responses

Abstract Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. However, the neuropathogenesis of POD remains mostly unknown. The prefrontal cortex (PFC) plays an essential role in cognitive processes. We therefore investigated how anesthesia and surgery induce neurofunctional changes in the PFC, and assessed whether intraoperative administration of dexmedetomidine, an alpha-2 agonist, could prevent the functional changes in the PFC. Laparotomy was performed in mice under isoflurane anesthesia. After a battery of behavioral tests measuring natural behaviors and learning and anxiety levels, PFC neuronal activities were recorded using whole-cell patch-clamp recordings. Effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. Intraoperative dexmedetomidine or glutamate receptor antagonists, prevented the excitatory synaptic dysfunction induced by anesthesia and surgery. These findings suggest that anesthesia and surgery induce functional reductions selectively in excitatory synaptic responses in PFC pyramidal neurons, and intraoperative dexmedetomidine inhibits the plastic change in the PFC synaptic transmission.

scholarly journals Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Rats

2021 ◽  
Author(s):  
Nawshaba Nawreen ◽  
Mark L Baccei ◽  
James P Herman
Keyword(s):  
Prefrontal Cortex ◽  
Traumatic Stress ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Intrinsic Excitability ◽  
Repetitive Firing ◽  
Membrane Excitability ◽  
Single Prolonged Stress ◽  
Prolonged Stress ◽  
Synaptic Drive

ABSTRACTPost-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed one week of recovery following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.Graphical AbstractSPS causes a decrease in excitatory synaptic drive and intrinsic excitability of IL pyramidal neurons.

scholarly journals Region-specific effects of HIV-1 Tat on intrinsic electrophysiological properties of pyramidal neurons in mouse prefrontal cortex and hippocampus

2020 ◽  
Vol 123 (4) ◽  
pp. 1332-1341 ◽  
Author(s):  
Thomas J. Cirino ◽  
Scott W. Harden ◽  
Jay P. McLaughlin ◽  
Charles J. Frazier
Keyword(s):  
Human Immunodeficiency Virus ◽  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Intrinsic Excitability ◽  
Tat Protein ◽  
Electrophysiological Properties ◽  
Specific Effects ◽  
Immunodeficiency Virus ◽  
Transactivator Of Transcription ◽  
Hiv 1

Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg·kg−1·day−1 ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND. NEW & NOTEWORTHY We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.

scholarly journals Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions

2015 ◽  
Vol 112 (26) ◽  
pp. 8106-8111 ◽  
Author(s):  
Manabu Fuchikami ◽  
Alexandra Thomas ◽  
Rongjian Liu ◽  
Eric S. Wohleb ◽  
Benjamin B. Land ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Neuronal Activity ◽  
Pyramidal Neurons ◽  
Rodent Models ◽  
Cellular Mechanisms ◽  
Optogenetic Stimulation ◽  
Layer V ◽  
And Function ◽  
Stimulation Of ◽  
Synaptic Responses

Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.

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