scholarly journals Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

2021 ◽  
Vol 22 (24) ◽  
pp. 13604
Author(s):  
Paulina Kazmierska-Grebowska ◽  
Marcin Siwiec ◽  
Joanna Ewa Sowa ◽  
Bartosz Caban ◽  
Tomasz Kowalczyk ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Medial Septum ◽  
Movement Planning ◽  
Theta Oscillations ◽  
Hcn Channels ◽  
Whole Cell Patch Clamp ◽  
Anaesthetized Rats ◽  
Ca1 Pyramidal Neuron

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

scholarly journals Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

2021 ◽  
Author(s):  
Paulina Kazmierska-Grebowska ◽  
Marcin Siwiec ◽  
Joanna Ewa Sowa ◽  
Caban Bartosz ◽  
Tomasz Kowalczyk ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Medial Septum ◽  
Movement Planning ◽  
Theta Oscillations ◽  
Hcn Channels ◽  
Anaesthetized Rats ◽  
Hippocampal Theta

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with various disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ionic) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel activator, and antiepileptic and neuroprotective agent, would affect hippocampal theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 and CA1 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine also depressed hippocampal theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in hippocampal neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

scholarly journals Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

2021 ◽  
Author(s):  
Paulina Kazmierska-Grebowska ◽  
Marcin Siwiec ◽  
Joanna Ewa Sowa ◽  
Bartosz Caban ◽  
Tomasz Kowalczyk ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Medial Septum ◽  
Movement Planning ◽  
Theta Oscillations ◽  
Hcn Channels ◽  
Anaesthetized Rats ◽  
Hippocampal Theta

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with various disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ionic) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel activator, and antiepileptic and neuroprotective agent, would affect hippocampal theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 and CA1 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine also depressed hippocampal theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in hippocampal neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

2001 ◽  
Vol 280 (6) ◽  
pp. R1815-R1822 ◽  
Author(s):  
Javier E. Stern ◽  
Mike Ludwig
Keyword(s):  
Neuronal Excitability ◽  
Cell Types ◽  
Synaptic Activity ◽  
No Donor ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Neuronal Types ◽  
Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih

2016 ◽  
Vol 26 (08) ◽  
pp. 1650044 ◽  
Author(s):  
Lihua Wang ◽  
Suzie Dufour ◽  
Taufik A. Valiante ◽  
Peter L. Carlen
Keyword(s):  
Neuronal Excitability ◽  
Seizure Activity ◽  
Membrane Properties ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Hcn Channels ◽  
Extracellular Potassium Concentration ◽  
Prolonged Seizure

Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP). However, when [K[Formula: see text]]o reached higher than 9[Formula: see text]mM, seizure like events (SLEs) were blocked and neurons went into a depolarization-blocked state. Spreading depression was never observed as the blockade of ictal events could be reversed within 1–2[Formula: see text]min after the raised [K[Formula: see text]]o was changed back to control levels. This concentration-dependent dual effect of [K[Formula: see text]]o was observed using in vivo and in vitro mouse brain preparations as well as in human neocortical tissue resected during epilepsy surgery. Blocking the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, modulated the elevated [K[Formula: see text]]o influence on SLEs by promoting the high [K[Formula: see text]]o inhibitory actions. These results demonstrate biphasic actions of raised [K[Formula: see text]]o on neuronal excitability and seizure activity.

scholarly journals Locomotion induced by medial septal glutamatergic neurons is linked to intrinsically generated persistent firing

2021 ◽  
Author(s):  
Karolína Korvasová ◽  
Felix Ludwig ◽  
Hiroshi Kaneko ◽  
Liudmila Sosulina ◽  
Tom Tetzlaff ◽  
...  
Keyword(s):  
Medial Septum ◽  
Theta Oscillations ◽  
Intrinsic Excitability ◽  
Theta Oscillation ◽  
Glutamatergic Neurons ◽  
Transient Activation ◽  
Persistent Firing ◽  
Septal Neurons

AbstractMedial septal glutamatergic neurons are active during theta oscillations and locomotor activity. Prolonged optogenetic activation of medial septal glutamatergic neurons drives theta oscillations and locomotion for extended periods of time outlasting the stimulus duration. However, the cellular and circuit mechanisms supporting the maintenance of both theta oscillations and locomotion remain elusive. Specifically, it remains unclear whether the presence of theta oscillations is a necessary prerequisite for locomotion, and whether neuronal activity within the medial septum underlies its persistence. Here we show that a persistent theta oscillation can be induced by a brief transient activation of glutamatergic neurons. Moreover, persistent locomotion is initiated even if the theta oscillation is abolished by blocking synaptic transmission in the medial septum. We observe persistent spiking of medial septal neurons that outlasts the stimulus for several seconds, both in vivo and in vitro. This persistent activity is driven by intrinsic excitability of glutamatergic neurons.

scholarly journals Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Anna R Moore ◽  
Sarah E Richards ◽  
Katelyn Kenny ◽  
Leandro Royer ◽  
Urann Chan ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Ocular Dominance ◽  
Sensory Experience ◽  
Cellular Level ◽  
Synaptic Function ◽  
Intrinsic Excitability ◽  
Spontaneous Firing ◽  
Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

scholarly journals K+ channel blockade in the NTS alters efficacy of two cardiorespiratory reflexes in vivo

1998 ◽  
Vol 274 (3) ◽  
pp. R677-R685 ◽  
Author(s):  
James W. Butcher ◽  
Julian F. R. Paton
Keyword(s):  
Potassium Channel ◽  
Neuronal Excitability ◽  
Baroreceptor Reflex ◽  
Right Atrial ◽  
K Channel ◽  
Reflex Bradycardia ◽  
Potassium Conductances ◽  
Voltage Dependent

We investigated the role of potassium conductances in the nucleus of the solitary tract (NTS) in determining the efficacy of the baroreceptor and cardiopulmonary reflexes in anesthetized rats. The baroreceptor reflex was elicited with an intravenous injection of phenylephrine to evoke a reflex bradycardia, and the cardiopulmonary reflex was evoked with a right atrial injection of phenylbiguanide. Microinjection of two Ca-dependent potassium channel antagonists (apamin and charybdotoxin) into the NTS potentiated the baroreceptor reflex bradycardia. This may reflect the increased neuronal excitability observed previously in vitro with these blockers. In contrast, the Ca-dependent potassium channel antagonists attenuated the cardiopulmonary reflex, whereas voltage-dependent potassium channel antagonists (4-aminopyridine and dendrotoxin) attenuated both the baro- and cardiopulmonary reflexes when microinjected into the NTS. The possibility that the reflex attenuation observed indicates a predominant distribution of certain potassium channels on γ-aminobutyric acid interneurons is discussed.

scholarly journals Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex

2018 ◽  
Vol 29 (9) ◽  
pp. 3778-3795
Author(s):  
Alexandre Pons-Bennaceur ◽  
Vera Tsintsadze ◽  
Thi-thien Bui ◽  
Timur Tsintsadze ◽  
Marat Minlebaev ◽  
...  
Keyword(s):  
Human Population ◽  
Temporal Summation ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Treatment Strategies ◽  
Anticonvulsant Treatment ◽  
A1 Receptor ◽  
Adenosine Signaling

Abstract Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/−), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/− mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

scholarly journals A Possible Link Between HCN Channels and Depression

2018 ◽  
Vol 2 ◽  
pp. 247054701878778 ◽  
Author(s):  
Chung Sub Kim ◽  
Daniel Johnston
Keyword(s):  
Protein Expression ◽  
Neuronal Excitability ◽  
Acute Stress ◽  
Hcn Channels ◽  
Chronic Unpredictable Stress ◽  
Ca1 Neurons ◽  
Ca1 Region ◽  
Hcn1 Channels ◽  
The Brain

Growing evidence suggests a possible link between hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels and depression. In a recent study published in Molecular Psychiatry, we first demonstrate that Ih (the membrane current mediated by HCN channels) and HCN1 protein expression were increased in dorsal, but not in ventral, CA1 region following chronic, but not acute stress. This upregulation of Ih was restricted to the perisomatic region of CA1 neurons and contributed to a reduction of neuronal excitability. A reduction of HCN1 protein expression in dorsal CA1 region before the onset of chronic unpredictable stress-induced depression was sufficient to provide resilient effects to chronic unpredictable stress. Furthermore, in vivo block of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, a manipulation known to increase intracellular calcium levels and upregulate Ih, produced anxiogenic-like behavior and an increase in Ih, similar to that observed in chronic unpredictable stress model of depression. Here, we share our view on (1) how the function and expression of HCN1 channels are changed in the brain in a subcellular region-specific manner during the development of depression and (2) how a reduction of HCN1 protein expression provides resilience to chronic stress.

scholarly journals Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition

2016 ◽  
Vol 116 (3) ◽  
pp. 1093-1103 ◽  
Author(s):  
Michael E. Authement ◽  
Ludovic D. Langlois ◽  
Haifa Kassis ◽  
Shawn Gouty ◽  
Matthieu Dacher ◽  
...  
Keyword(s):  
Behavioral Plasticity ◽  
Drugs Of Abuse ◽  
Patch Clamp Recording ◽  
Whole Cell Patch Clamp ◽  
Synaptic Changes ◽  
Induced Changes ◽  
And Behavior ◽  
H3 Acetylation

Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.

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