Alterations in the intrinsic discharge activity of CA1 pyramidal neurons associated with possible changes in the NADPH diaphorase activity in a rat model of autism induced by prenatal exposure to valproic acid.

Autism spectrum disorder is a neurodevelopmental disorder characterized by sensory abnormalities, social skills impairment and cognitive deficits. Although recent evidence indicated that induction of autism-like behavior in animal models causes abnormal neuronal excitability, the impact of autism on neuronal properties is still an important issue. Thus, new findings at the cellular level may shed light on the pathophysiology of autism and may help to find effective treatment strategies. Here, we investigated the behavioral, electrophysiological and histochemical impacts of prenatal exposure to valproic acid (VPA) in rats. Findings revealed that VPA exposure caused a significant increase in the hot plate response latency. The novel object recognition ability was also impaired in VPA-exposed rats. Along with these behavioral alterations, neurons from VPA-exposed animals exhibited altered excitability features in response to depolarizing current injections relative to control neurons. In the VPA-exposed group, these changes consisted of a significant increase in the amplitude, evoked firing frequency and the steady-state standard deviation of spike timing of action potentials (APs). Moreover, the half-width, the AHP amplitude and the decay time constant of APs were significantly decreased in this group. These changes in the evoked electrophysiological properties were accompanied by intrinsic hyperexcitability and lower spike-frequency adaptation and also a significant increase in the number of NADPH-diaphorase stained neurons in the hippocampal CA1 area of the VPA-exposed rats. Taken together, findings demonstrate that abnormal nociception and recognition memory is associated with alterations in the neuronal responsiveness and nitrergic system in a rat model of autism-like.

Kisspeptin-13 prevented the electrophysiological alterations induced by amyloid-beta pathology in rat: Possible involvement of stromal interaction molecules and pCREB.

Alzheimer's disease (AD) is a progressive neurological disease that slowly causing memory impairments with no effective treatment. We have recently reported that kisspeptin-13 (KP-13) ameliorates Aß toxicity-induced memory deficit in rats. Here, the possible cellular impact of kisspeptin receptor activation in a rat model of the early stage AD was assessed using whole-cell patch-clamp recording from CA1 pyramidal neurons and molecular approaches. Compared to neurons from the control group, cells from the Aß-treated group displayed spontaneous and evoked hyperexcitability with lower spike frequency adaptation. These cells had also a lower sag ratio in response to hyperpolarizing prepulse current delivered before a depolarizing current injection. Neurons from the Aß-treated group exhibited short spike onset latency, lower rheobase and short utilization time compared with those in the control group. Furthermore, phase plot analysis of action potential showed that Aß treatment affected the action potential features. These electrophysiological changes induced by Aß were associated with increased expression of stromal interaction molecules (STIMs), particularly (STIM2) and decreased pCREB/CREB ratio. Treatment with KP-13 following Aß injection into the entorhinal cortex, however, prevented the excitatory effect of Aß on spontaneous and evoked neuronal activity, increased the latency of onset, enhanced the sag ratio, increased the rheobase and utilization time, and prevented the changes induced Aß on spike parameters. In addition, the KP-13 application after Aß treatment reduced the expression of STIMs and increased the pCREB/CREB ratio compared to those receiving Aß treatment alone. In summary, these results provide evidence that activation of kisspeptin receptor may be effective against pathology of Aß.

Investigating the Cocaine-induced Reduction of Potassium Current on the Generation of Action Potentials Using a Computational Model.

Introduction: Drugs of abuse, such as cocaine, affect different brain regions and lead to pathological memories. These abnormal memories may occur due to changes in synaptic transmissions or variations in synaptic properties of neurons. It has been shown that cocaine inhibits delayed rectifying potassium currents in affected brain regions and can create pathological memories.This study investigates how the change in the conductance of delayed rectifying potassium channels can affect the produced action potentials using a computational model. Methods: We present a computational model with different channels and receptors, including sodium, potassium, calcium, NMDARs, and AMPARs, which can produce burst-type action potentials. In the simulations, by changing the delayed rectifying potassium conductance bifurcation diagram is calculated. Results: By decreasing the potassium current for a fixed stimulatory signal, burst-type action potentials can be generated. In the following and with a further reduction of potassium conductance, produced action potentials exhibit non-linear and even chaotic behaviors. Conclusion: Results show that for a specific range of potassium conductance, a chaotic regime emerges in produced action potentials. These chaotic oscillations may play a role in inducing abnormal memories. Highlights: Cocaine consumption reduces the potassium current in affected cells.Decreasing the potassium currents elicits burst action potentials.Produced bursts might have chaotic behaviors.Chaotic oscillations might be related to the toxic effects of cocaine. Plain Language Summary: Drugs of abuse such as cocaine can manipulate brain circuits and may form some pathological memories. These memories can lead to long-term addiction. Furthermore, these drugs also can have toxic effects on the cells. Researchers are looking for the mechanisms that can lead to abnormal memories and toxic effects of drugs. It seems that an efficient mechanism that can be used by drugs of abuse is the manipulation of potassium currents in the affected cells. Here, in a computational model, we have shown that changes in the conductance of delayed rectifying potassium channels can lead to nonlinear and even chaotic behaviors in the produced action potentials. These behaviors might have a role in drug toxic effects.

Ca2+ Channels Involvement in Low-Frequency Stimulation-Mediated Suppression of Intrinsic Excitability of Hippocampal CA1 Pyramidal Cells in a Rat Amygdala Kindling Model.

Low-frequency stimulation has demonstrated promising seizure suppression in animal models of epilepsy, while the mechanism of the effect is still debated. Changes in intrinsic properties have been recognized as a prominent pathophysiologically relevant feature of numerous neurological disorders including epilepsy. Here, it was evaluated whether LFS can preserve the intrinsic neuronal electrophysiological properties in a rat model of epilepsy, focusing on the possible involvement of voltage-gated Ca2+ channels. The amygdala kindling model was induced by 3 s monophasic square wave pulses (50 Hz, 1 ms duration, 12times/day at 5 min intervals). Both LFS alone and kindled plus LFS (KLFS) groups received four packages of LFS (each consisting of 200 monophasic square pulses, 0.1 ms pulse duration at 1 Hz with the after discharge threshold intensity), which in KLFS rats was applied immediately after kindling induction. Whole-cell patch-clamp recordings were made in the presence of fast synaptic blockers 24 h after the last kindling stimulations or following kindling stimulations plus LFS application. In the KLFS group, both the rebound excitation and kindling-induced intrinsic hyperexcitability were decreased, associated with a regular intrinsic firing as indicated by a lower coefficient of variation. The amplitude of afterdepolarization (ADP) and its area under the curve were both decreased in the KLFS group compared to the kindled group. LFS prevented the increasing effect of kindling on Ca2+ currents in the KLFS group. Findings provided evidence for a novel form of epileptiform activity suppression by LFS in the presence of synaptic blockade possibly by decreasing Ca2+ currents.

Hyperexcitability of hippocampal CA1 pyramidal neurons in male offspring of a rat model of autism spectrum disorder (ASD) induced by prenatal exposure to valproic acid: A possible involvement of Ih channel current.

Autism spectrum disorder (ASD) is a common neuropsychiatric disorder, which is characterized by impairment in social interaction and cognitive behaviors. However, there is not much electrophysiological data available on alterations of neuronal excitability in autism. Here, we assessed the pattern of neuronal excitability and the possible contribution of Ih current to the altered excitability of hippocampal CA1 pyramidal neurons in a rat model of VPA-induced ASD-like behavior. Pregnant Wistar rats received valproic acid (VPA, 500 mg/kg) at gestational day 12.5. All offspring were subjected to behavioral tests to verify the induction of ASD-like behaviors. On postnatal day (PND) 45, whole-cell patch-clamp recordings were performed on hippocampal CA1 pyramidal neurons in slices obtained from control and prenatal VPA-exposed pups, under current and voltage-clamp conditions. Our results showed that beside the induction of behavioral abnormalities in ASD pups, higher excitability of hippocampal CA1 pyramidal neurons was also prominent, as evidenced by a significant increase in the spontaneous firing frequency and evoked firing rate, as well as a significant decrease in the rheobase current. In the VPA-exposed group, the steady-state (ISS) Ih current amplitude was significantly smaller than control cells. The Ih half-activation voltage shifted toward more negative potentials in the VPA-exposed group. The sag ratio was also significantly less than the control cells. Moreover, the cell soma size was shifted toward smaller diameter in VPA-exposed group. Overall, induction of ASD-like behaviors was associated with neuronal hyperexcitability, which, at least in part, could be attributed to the changes in Ih channels function.

Assessing the Effects of Opioids on Pathological Memory by a Computational Model.

INTRODUCTION: Opioids hijack learning and memory formation mechanisms of brain and induce a pathological memory in the hippocampus. This effect is mainly mediated by modifications in glutamatergic system. Speaking more precisely, Opioids presence in a synapse inhibits blockage of N-Methyl-D-Aspartate Receptor (NMDAR) by Mg2+, enhances conductance of NMDAR and thus, induces false Long-Term Potentiation (LTP). METHODS: Based on experimental observations of different researchers, we developed a mathematical model for a pyramidal neuron of the hippocampus to study this false LTP. The model contains a spine of the pyramidal neuron with NMDAR, α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptors (AMPARs), and Voltage-Gated Calcium Channels (VGCCs). The model also describes Calmodulin-dependent protein Kinase II (CaMKII) and AMPAR phosphorylation processes which are assumed to be the indicators of LTP induction in the synapse. RESULTS: Simulation results indicate that the effect of inhibition of blockage of NMDARs by Mg2+ on the false LTP is not as crucial as the effect of NMDAR's conductance modification by opioids. We also observed that activation of VGCCs has a dominant role in inducing pathological LTP. CONCLUSION: Our results confirm that preventing this pathological LTP is possible by three different mechanisms: 1. By decreasing NMDAR's conductance; and 2. By attenuating VGCC's mediated current; and 3. By enhancing glutamate clearance rate from the synapse.

Formation of Opioid-Induced Memory and Its Prevention: A Computational Study.

There are several experimental studies which suggest opioids consumption forms pathological memories in different brain regions. For example it has been empirically demonstrated that the theta rhythm which appears during chronic opioid consumption is correlated with the addiction memory formation. In this paper, we present a minimal computational model that shows how opioids can change firing patterns of the neurons during acute and chronic opioid consumption and also during withdrawal periods. The model consists of a pre- and post-synaptic neuronal circuits and the astrocyte that monitors the synapses. The output circuitry consists of inhibitory interneurons and excitatory pyramidal neurons. Our simulation results demonstrate that acute opioid consumption induces synchronous patterns in the beta frequency range, while, chronic opioid consumption provokes theta frequency oscillations. This allows us to infer that the theta rhythm appeared during chronic treatment can be an indication of brain engagement in opioid-induced memory formation. Our results also suggest that changing the inputs of the interneurons and the inhibitory neuronal network is not an appropriate method for preventing the formation of pathological memory. However, the same results suggest that prevention of pathological memory formation is possible by manipulating the input of the stimulatory network and the excitatory connections in the neuronal network. They also show that during withdrawal periods, firing rate is reduced and random fluctuations are generated in the modeled neural network. The random fluctuations disappear and synchronized patterns emerge when the activities of the astrocytic transporters are decreased. These results suggest that formation of the synchronized activities can be correlated with the relapse. Our model also predicts that reduction in gliotransmitter release can eliminate the synchrony and thereby it can reduce the likelihood of the relapse occurrence.

Computational modeling of opioid-induced synaptic plasticity in hippocampus.

According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP. To this purpose, a detailed computational model is presented, which consists of one pyramidal neuron and one interneuron both from CA3, one CA1 pyramidal neuron, and one astrocyte. Based on experimental findings morphine affects the hippocampal neurons in three primary ways: 1) disinhibitory mechanism of interneurons in CA3, 2) enhancement of NMDARs current by µ Opioid Receptor (µOR) activation and 3) by attenuation of astrocytic glutamate reuptake ability. By utilizing these effects, simulations were implemented. Our results indicate that morphine can induce LTP by all aforementioned possible mechanisms. Based on our simulation results, attenuation of pathologic LTP achieved mainly by stimulation of astrocytic glutamate transporters, down-regulation of the astrocytic metabotropic glutamate receptors (mGlurs) or by applying NMDAR's antagonist. Based on our observations, we suggest that astrocyte has a dominant role in forming addiction-related memories. This finding may help researchers in exploring drug actions for preventing relapse.