The differential effects of blocking retinal orexin receptors on the expression of retinal c-fos and hypothalamic Vip, PACAP, Bmal1, and c-fos in Male Wistar Rats.

Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and c-fos, as well as hypothalamic c-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 11, and ZT-0). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated c-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. Moreover, the expression of hypothalamic Vip and PACAP was significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Furthermore, the expression of hypothalamic c-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. Additionally, the study demonstrated that blocking these receptors in the retina resulted in alterations in circadian rhythm parameters such as mesor, amplitude, and acrophase. Finally, it affected the phase of gene expression rhythms in both the retina and hypothalamus, as identified through cosinor analysis and the zero-amplitude test. This study represents the initial exploration of how retinal orexin receptors influence expression of rhythmic genes in the retina and hypothalamus. These findings could provide new insights into how the retina regulates the circadian rhythm in both regions and illuminate the role of the orexinergic system expression within the retina.

Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aß) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aß25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aß25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aß25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aß25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aß25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aß on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

Pharmacologic antagonism of CB1 receptors improves electrophysiological alterations in Purkinje cells exposed to 3-AP.

INTRODUCTION: Although ataxia is associated with cerebellar dysfunction, little is known about the effects of 3-AP exposure on Purkinje cell electrophysiological properties. Here, we evaluated these parameters in cerebellar vermis brain slices. METHODS: Purkinje cells were exposed to artificial cerebrospinal fluid (aCSF) (control) or to 1 mM 3-acetylpyridine (3-AP) in the recording chamber. The effects of a cannabinoid agonist (WIN; 7.5 nmol) and a cannabinoid antagonist (AM; 20 nmol) were evaluated under both conditions. RESULTS: Exposure to 3-AP induced dramatic changes in cellular excitability that likely would affect Purkinje cell output. In whole-cell current clamp recordings, 3-AP-exposed Purkinje cells demonstrated a significantly higher frequency of action potentials, a larger afterhyperpolarization (AHP), and a larger rebound of action potentials. In addition, 3-AP caused a significant decrease in the interspike interval (ISI), half-width, and first spike latency. Remarkably, the action potential frequency, AHP amplitude, rebound, ISI, action potential halfwidth, and first spike latency were no longer different from controls in 3-AP cells treated with AM. Sag percentage, on the other hand, showed no significant difference under any treatment condition, indicating that cannabinoids' actions on 3-AP-mediated Purkinje cell changes may not include effects on neuronal excitability through changes of Ih. CONCLUSIONS: These data show that cannabinoid antagonists reduce the excitability of Purkinje cells following exposure to 3-AP and suggest their potential as therapeutics in cerebellar dysfunctions.

The Glycolysis Inhibitor 2-Deoxy-D-Glucose Exerts Different Neuronal Effects at Circuit and Cellular Levels, Partially Reverses Behavioral Alterations and does not Prevent NADPH Diaphorase Activity Reduction in the Intrahippocampal Kainic Acid Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy is the most drug-resistant type with the highest incidence among the other focal epilepsies. Metabolic manipulations are of great interest among others, glycolysis inhibitors like 2-deoxy D-glucose (2-DG) being the most promising intervention. Here, we sought to investigate the effects of 2-DG treatment on cellular and circuit level electrophysiological properties using patch-clamp and local field potentials recordings and behavioral alterations such as depression and anxiety behaviors, and changes in nitric oxide signaling in the intrahippocampal kainic acid model. We found that epileptic animals were less anxious, more depressed, with more locomotion activity. Interestingly, by masking the effect of increased locomotor activity on the parameters of the zero-maze test, no altered anxiety behavior was noted in epileptic animals. However, 2-DG could partially reverse the behavioral changes induced by kainic acid. The findings also showed that 2-DG treatment partially suppresses cellular level alterations while failing to reverse circuit-level changes resulting from kainic acid injection. Analysis of NADPH-diaphorase positive neurons in the CA1 area of the hippocampus revealed that the number of positive neurons was significantly reduced in dorsal CA1 of the epileptic animals and 2-DG treatment did not affect the diminishing effect of kainic acid on NADPH-d+ neurons in the CA1 area. In the control group receiving 2-DG, however, an augmented NADPH-d+ cell number was noted. These data suggest that 2-DG cannot suppress epileptiform activity at the circuit-level in this model of epilepsy and therefore, may fail to control the seizures in temporal lobe epilepsy cases.

Inhibition of the retinal orexin receptors affects the hypothalamic-pituitary-gonadal axis through retinal pituitary adenylate cyclase activating polypeptide (PACAP) in male Wistar rats.

Orexins A and B (OXA and OXB) and their receptors are expressed in the retina of both human and rodents and play a vital role in regulating signal transmission circuits in the retina. There is an anatomical-physiological relationship between the retinal ganglion cells and suprachiasmatic nucleus (SCN) through glutamate as a neurotransmitter and retinal pituitary adenylate cyclase-activating polypeptide (PACAP) as a co-transmitter. SCN is the main brain center for regulating the circadian rhythm, which governs the reproductive axis. The impact of retinal orexin receptors on the hypothalamic-pituitary-gonadal axis has not been investigated. Retinal OX1R or/and OX2R in adult male rats by 3 µl of SB-334867 (1 µg) or/and 3 µl of JNJ-10397049 (2 µg) were antagonized via intravitreal injection (IVI). Four time-periods were considered (3, 6, 12, and 24 h) for the controls without any treatment, SB-334867, JNJ-10397049, and SB-334867 + JNJ-10397049 groups. Antagonizing retinal OX1R or/and OX2R resulted in a significant elevation of retinal PACAP expression compared to control animals. In addition, expression of GnRH increased non-significantly in the hypothalamus over the 6 h of the study, and the serum concentration of LH decreased significantly in the SB-334867 group after 3 h of injection. Furthermore, testosterone serum levels declined significantly, especially within 3 h of injection; serum levels of progesterone were also exposed to a significant rise at least within 3 h of injection. However, the retinal PACAP expression changes were mediated by OX1R more effectively than by OX2R. In this study, we report the retinal orexins and their receptors as light-independent factors by which the retina affects the hypothalamic-pituitary-gonadal axis.

Preventive putative effect of agmatine on cognitive and molecular outcomes in ventral tegmental area of male offspring following physical and psychological prenatal stress.

Prenatal stress (PS) results from a maternal experience of stressful events during pregnancy, which has been associated with an increased risk of behavioral disorders including substance abuse and anxiety in the offspring. PS is known to result in heightened dopamine release in the ventral tegmental area (VTA), in part through the effects of corticotropin-releasing hormone, which directly excites dopaminergic cells. It has recently been suggested that agmatine plays a role in modulating anxiety-like behaviors. In this study, we investigated whether agmatine could reduce negative cognitive outcomes in male mice prenatally exposed to psychological/physical stress, and whether this could be associated with molecular changes in VTA. Agmatine (37.5 mg/kg) was administrated 30 min prior to PS induction in pregnant Swiss mice. Male offspring were evaluated in a series of behavioral and molecular assays. Findings demonstrated that agmatine reduced the impairment in locomotor activity induced by both psychological and physical PS. Agmatine also decreased heightened conditioned place preference to morphine seen in PS offspring. Moreover, agmatine ameliorated the anxiety-like behavior and drug-seeking behavior induced by PS in the male offspring. Molecular effects were seen in VTA as the enhanced brain-derived neurotrophic factor (BDNF) induced by PS in the VTA was reduced by agmatine. Behavioral tests indicate that agmatine exerts a protective effect on PS-induced impairments in male offspring, which could be due in part to agmatine-associated molecular alterations in the VTA. Taken together, our data suggest that prenatal treatment with agmatine exerts protective effect against negative consequences of PS on the development of affective circuits in the offspring.

Modulation of the CB1 cannabinoid receptor has potential therapeutic utility in the 3-acetylpyridine cerebellar ataxia rat model.

Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212-2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.

Glial cells inhibition affects the incidence of metaplasticity in the hippocampus of Pentylentetrazole-induced kindled rats.

Epilepsy is characterized by the unpredictability but recurrence of seizures caused by the synchronized aberrant firing of neuronal populations. It has been shown that astrocytes (one of the most prominent glial cells) are ideally positioned to induce or contribute to neural network synchronization. Although astrocytes cannot generate action potentials, they have the capacity to sense and respond to neuronal activity, which allows them to function as homeostatic regulators of synaptic interactions. Considering the necessity of astrocyte-neuron bidirectional interactions in synaptic transmission and plasticity, in the current study, the role of astrocytes in synaptic metaplasticity and resultant behavioral seizures induced by Pentylentetrazole (PTZ) was assessed. Rats were kindled by intraperitoneal (i.p.) injection of PTZ (30 mg/kg/48 h). A glial cell inhibitor, Fluorocitrate (FC), was injected into the right lateral cerebral ventricle of the rat 30 min before PTZ during kindling progress. The maximal seizure stage (SS), stage 2 and 4 latency (S2L, S4L), stage 4 and 5 duration (S4D, S5D), and seizure duration (SD) were all assessed 20 min after PTZ administration by observation. Following Schaffer collateral stimulation, in vivo field, potential recordings from the CA1 area of the hippocampus were employed to assess the metaplasticity induced in kindled rats. The inhibition of glial cells during the kindling process significantly lowered SS, S4D&S5D and increased S4L (Two-way ANOVA, Bonferroni Posttest, P < 0.05, P < 0.01, and P < 0.001). In comparison to the control group, electrophysiological data demonstrated that HFS-induced LTP in kindled animals was decreased (Unpaired t-test, P < 0.05). Glial cell inhibition prevented PTZ's effect on LTP. Our data imply that kindling altered CA1 pyramidal neurons' vulnerability to synaptic plasticity. This shift in neuronal plasticity (metaplasticity) is mediated in part by glial cells and is important in the formation of seizure symptoms. As a result, glial cell inhibition was found to alleviate seizure behavior.

The effects of glial cells inhibition on spatial reference, reversal and working memory deficits in a rat model of traumatic brain injury (TBI).

AIMS: Evidence suggests that glial cells are influenced by Traumatic brain injury (TBI). Both protective and damaging roles have been attributed to reactive glial cells, but their role after TBI has not been well understood. In this study, the role of glial cells in TBI-induced cognitive impairment was investigated. MATERIALS AND METHODS: Male rats were randomly assigned to the following groups: Sham + PBS, sham + FC, TBI + PBS, and TBI + FC. FC (1 nmol/1 µl), a glial cell inhibitor, was injected into the lateral ventricle 10 min after TBI induction and it was repeated every 24 h until the seventh day. On days 8-13 post-injury, reference and reverse memory and on days 8-16 post-injury, working memory was assessed using the Morris water maze test. RESULTS: Brain-injured rats exhibited significant impairments in acquisition and retrieval phases of reference and reverse memory compared to sham rats and FC administration could not attenuate the deteriorative effect of TBI in different learning tasks. TBI rats showed impairment in acquisition (but not retrieval) of working memory. Sham animals which received FC showed a deficit in reversal memory acquisition and retrieval of reference memory compared to sham + PBS rats. CONCLUSION: The present study demonstrates that memory deficit induced by TBI cannot be improved by FC, and glial cells inhibition in uninjured animals causes impairments in reversal memory acquisition and retrieval of reference memory. Our results suggest that in addition to essential role of glial cells for memory formation in normal situation, their responses after TBI may have preventive effect against memory impairments.

Enhancement of intrinsic neuronal excitability-mediated by a reduction in hyperpolarization-activated cation current (Ih ) in hippocampal CA1 neurons in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) is associated with epileptiform activity in the hippocampus; however, the underlying mechanisms have not been fully determined. The goal was to understand what changes take place in intrinsic neuronal physiology in the hippocampus after blunt force trauma to the cortex. In this context, hyperpolarization-activated cation current (Ih ) currents may have a critical role in modulating the neuronal intrinsic membrane excitability; therefore, its contribution to the TBI-induced hyperexcitability was assessed. In a model of TBI caused by controlled cortical impact (CCI), the intrinsic electrophysiological properties of pyramidal neurons were examined 1 week after TBI induction in rats. Whole-cell patch-clamp recordings were performed under current- and voltage-clamp conditions following ionotropic receptors blockade. Induction of TBI caused changes in the intrinsic excitability of pyramidal neurons, as shown by a significant increase and decrease in firing frequency and in the rheobase current, respectively (p < .05). The evoked firing rate and the action potential time to peak were also significantly increased and decreased, respectively (p < .05). In the TBI group, the amplitude of instantaneous and steady-state Ih currents was both significantly smaller than those in the control group (p < .05). The Ih current density was also significantly decreased (p < .001). Findings indicated that TBI led to an increase in the intrinsic excitability in CA1 pyramidal neurons and changes in Ih current could be, in part, one of the underlying mechanisms involved in this hyperexcitability.

5-HT7 receptor activation rescues impaired synaptic plasticity in an autistic-like rat model induced by prenatal VPA exposure.

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.

Ameliorating Effects of Dorema ammoniacum on PTZ-Induced Seizures and Epileptiform Brain Activity in Rats.

The objective of the current study was to investigate the anti-epileptogenic and anticonvulsant effects of Dorema ammoniacum gum, which is used in Iranian traditional medicine for the treatment of seizures. Animals received pentylenetetrazol (IP, 30 mg/kg/48 h) for inducing seizures. Five different seizure stages were evaluated for 20 min and parameters including maximum seizure stage, the latency to the onset of stage 4, stage 4 duration, and seizure duration were measured. D. ammoniacum (50 and 100 mg/kg) or its vehicle was administered 30 min before or after pentylenetetrazol injection in different groups. In addition, the effective dose of D. ammoniacum (100 mg/kg) on different seizure stages was compared with the common antiseizure drug phenobarbital. In another set of experiments, we investigated the effective dose of D. ammoniacum on fully kindled animals in which an interictal electroencephalogram was recorded by superficial electrodes placed on the skull. The results showed that D. ammoniacum administration, before and after pentylenetetrazol injections, significantly decreased seizure stage, seizure duration, stage 4 duration, and 1/stage 4 latency. The anti-epileptogenic effect of D. ammoniacum was about 50 to 60% of phenobarbital. In addition, D. ammoniacum significantly decreased seizure stage, seizure duration, stage 4 duration, and 1/stage 4 latency when administered to fully kindled animals but had no effect on the power of EEG sub-bands. These results indicate that D. ammoniacum has anti-epileptogenic and anticonvulsant effects in a chemical kindling model of seizures.

Study of the anti-seizure effects of low-frequency stimulation following kindling (a review of the cellular mechanism related to the anti-seizure effects of low-frequency electrical stimulation).

Epilepsy affects about 1-2 % of world population as a chronic neurological disease that is manifested by repeated and consecutive seizures (Grone and Baraban, Nat Neurosci 18(3):339-343, 2015). There is no definitive therapy for epilepsy and antiepileptic drugs cannot offer a permanent and definitive cure for epilepsy, and most epileptic patients become drug resistant (Sasa, J Pharmacol Sci 100(5):487-494, 2006). Surgery and removal of the epileptic focus is a substitute method for treating drug-resistant patients and epilepsy surgery of either side of the brain improves seizure control. Temporal lobectomy is the most common epilepsy surgery and is associated with high success rates. Other studies have reported higher success rates for carefully selected temporal lobe seizure patients. Some physicians still consider temporal lobectomy an extreme procedure, citing the risks of side effects, including loss of memory, visual disturbances, and emotional change, associated with the removal of brain tissue (Spencer, Lancet Neurol 1(6):375-382, 2002; Wiebe et al., N Engl J Med 345(5):311-318, 2001; Yasargil et al., J Neurosurg 112(1):168-185, 2010). Nowadays, direct electrical stimulation (in the form of low- or high-frequency stimulation) in the location involved in seizures is used as a potentially suitable treatment method for this destructive disease in both laboratory animals and humans (Goodman et al., Epilepsia 46(1):1-7, 2005; Richardson et al., Epilepsia 44(6):768-777, 2003; Velasco et al., Epilepsia 41(2):158-169, 2000). Low-frequency stimulation causes less damage to the epileptic area and surrounding neuronal structures compared to high-frequency stimulation, and it can be a suitable option for patients suffering from epilepsy (Goodman et al., Epilepsia 46(1):1-7, 2005). Since the cellular mechanism of this stimulation is not clearly known, the purpose of this review research was to investigate the anticonvulsive effects of low-frequency electrical stimulation and the probable cellular mechanism involved in it.

Calcium channel blockade attenuates abnormal synaptic transmission in the dentate gyrus elicited by entorhinal amyloidopathy.

Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Aß) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Aß treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Aß treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Aß in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Aß toxicity.

Alterations in the intrinsic burst activity of Purkinje neurons in offspring maternally exposed to the CB1 cannabinoid agonist WIN 55212-2.

Burst firing plays an important role in normal neuronal function and dysfunction. In Purkinje neurons, where the firing rate and discharge pattern encode the timing signals necessary for motor function, any alteration in firing properties, including burst activity, may affect the motor output. Therefore, we examined whether maternal exposure to the cannabinoid receptor agonist WIN 55212-2 (WIN) may affect the burst firing properties of cerebellar Purkinje cells in offspring. Whole-cell somatic patch-clamp recordings were made from cerebellar slices of adult male rats that were exposed to WIN prenatally. WIN exposure during pregnancy induced long-term alterations in the burst firing behavior of Purkinje neurons in rat offspring as evidenced by a significant increase in the mean number of spikes per burst (p < 0.05) and the prolongation of burst firing activity (p < 0.01). The postburst afterhyperpolarization potential (p < 0.001), the mean intraburst interspike intervals (p < 0.001) and the mean intraburst firing frequency (p < 0.001) were also significantly increased in the WIN-treated group. Prenatal exposure to WIN enhanced the firing irregularity as reflected by a significant decrease in the coefficient of variation of the intraburst interspike interval (p < 0.05). Furthermore, whole-cell voltage-clamp recordings revealed that prenatal WIN exposure significantly enhanced Ca(2+) channel current amplitude in offspring Purkinje neurons compared to control cells. Overall, the data presented here strongly suggest that maternal exposure to cannabinoids can induce long-term changes in complex spike burst activity, which in turn may lead to alterations in neuronal output.

Aquaporin-4 inhibition attenuates Pentylenetetrazole-induced behavioral seizures and cognitive impairments in kindled rats.

Epilepsy is a neurological condition distinguished by recurrent and unexpected seizures. Astrocytic channels and transporters are essential for maintaining normal neuronal functionality. The astrocytic water channel, aquaporin-4 (AQP4), which plays a pivotal role in regulating water homeostasis, is a potential target for epileptogenesis. In present study, we examined the effect of different doses (10, 50, 100 µM and 5 mM) of AQP4 inhibitor, 2-nicotinamide-1, 3, 4-thiadiazole (TGN-020), during kindling acquisition, on seizure parameters and seizure-induced cognitive impairments. Animals were kindled by injection of pentylenetetrazole (PTZ: 37.5 mg/kg, i.p.). TGN-020 was administered into the right lateral cerebral ventricle 30 min before PTZ every alternate day. Seizure parameters were assessed 20 min after PTZ administration. One day following the last PTZ injection, memory performance was investigated using spontaneous alternation in Y-maze and novel object recognition (NOR) tests. The inhibition of AQP4 during the kindling process significantly decreased the maximal seizure stage and seizure duration (two-way ANOVA, P = 0.0001) and increased the latency of seizure onset and the number of PTZ injections required to induce different seizure stages (one-way ANOVA, P = 0.0001). Compared to kindled rats, the results of the NOR tests showed that AQP4 inhibition during PTZ-kindling prevented recognition memory impairment. Based on these results, AQP4 could be involved in seizure development and seizure-induced cognitive impairment. More investigation is required to fully understand the complex interactions between seizure activity, water homeostasis, and cognitive dysfunction, which may help identify potential therapeutic targets for these conditions.

Photoacoustic viscoelasticity assessment of prefrontal cortex and cerebellum in normal and prenatal valproic acid-exposed rats.

Mechanical properties of brain tissues are from principal features from different points of view; diagnosis, the performance of the brain and neurological disorders. Particularly viscoelastic properties of the brain tissues are determinative. In this study based on a proposed accurate and non-invasive method, we have measured the viscoelastic properties of prefrontal cortex and cerebellum, two important brain regions involved in motor learning and pathophysiology of autism spectrum disorder (ASD). In this regard, using photoacoustic systems, viscoelastic properties of tissues from the cerebellum and prefrontal cortex of normal and prenatal VPA (Valproic acid)-exposed (i.e. autistic-like) offspring rats are measured. Results of our study show that the cerebellums of normal tissues are stiffer than the tissue obtained from autistic-like rats, while the viscoelasticity of the prefrontal cortex of normal tissues is higher than that of autistic ones. The proposed method for the measurement of viscoelastic properties of the brain tissue has the potential not only for the fundamental studies but as a diagnosis technique.

Social hierarchy differentially influences the anxiety-like behaviors and dendritic spine density in prefrontal cortex and limbic areas in male rats.

Social hierarchy is a fundamental feature of social organization that can influence brain and emotional processing regarding social ranks. Several areas, including the medial prefrontal cortex (mPFC), the hippocampus, and the basolateral nucleus of the amygdala (BLA), are recognized to be involved in the regulation of emotional processing. However, its delicate structural correlates in brain regions are poorly understood. To address this issue, social hierarchy in home-caged sibling Wistar rats (three male rats/cage) was determined by employing a social confrontation tube test (postnatal weeks 9-12). Then, locomotor activity and anxiety-like behaviors were evaluated using an open-field test (OFT) and elevated plus-maze (EPM) at 13 weeks of age. The rapid Golgi impregnation method was conducted to quantify the spine density of the first secondary branch of the primary dendrite in 20 µm length. The results indicated that dominant rats had significantly higher anxiety-like behaviors compared to subordinates, as was evident by lower open-arm entries and time spent in the EPM and lower entries and time spent in the center of OFT. The spine density analysis revealed a significantly higher number of spines in subordinates compared to the dominant rats in dmPFC pyramidal neurons and the apical and basal dendrites of hippocampal CA1 pyramidal neurons. However, the spine density of pyramidal-like neurons in the BLA was higher in dominant rats. Our findings suggest that dominant social rank is associated with higher anxiety and differential density of the dendritic spine in the prefrontal cortex and limbic regions of the brain in male rats.

Reversal of electrophysiological and behavioral deficits mediated by 5-HT7 receptor upregulation following LP-211 treatment in an autistic-like rat model induced by prenatal valproic acid exposure.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by alterations and imbalances in multiple brain neurochemical systems, particularly the serotonergic neurotransmission. This includes changes in serotonin (5-HT) levels, aberrations in 5-HT transporter activity, and decreased synthesis and expression of 5-HT receptors (5-HT7Rs). The exact role of the brain 5-HT system in the development of ASD remains unclear, with conflicting evidence on its involvement. Recently, we have reported research has shown a significant decrease in serotonergic neurons originating from the raphe nuclei and projecting to the CA1 region of the dorsal hippocampus in autistic-like rats. Additionally, we have shown that chronic activation of 5-HT7Rs reverses the effects of autism induction on synaptic plasticity. However, the functional significance of 5-HT7Rs at the cellular level is still not fully understood. This study presents new evidence indicating an upregulation of 5-HT7R in the CA1 subregion of the hippocampus following the induction of autism. The present account also demonstrates that activation of 5-HT7R with its agonist LP-211 can reverse electrophysiological abnormalities in hippocampal pyramidal neurons in a rat model of autism induced by prenatal exposure to VPA. Additionally, in vivo administration of LP-211 resulted in improvements in motor coordination, novel object recognition, and a reduction in stereotypic behaviors in autistic-like offspring. The findings suggest that dysregulated expression of 5-HT7Rs may play a role in the pathophysiology of ASD, and that agonists like LP-211 could potentially be explored as a pharmacological treatment for autism spectrum disorder.

Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments.

Neural synchronization is considered as an important mechanism for information processing. In addition, based on recent neurophysiologic findings, it is believed that astrocytes regulate the synaptic transmission of neuronal networks. Therefore, the present study focused on determining the functional contribution of astrocytes in neuronal synchrony using both computer simulations and extracellular field potential recordings. For computer simulations, as a first step, a minimal network model is constructed by connecting two Morris-Lecar neuronal models. In this minimal model, astrocyte-neuron interactions are considered in a functional-based procedure. Next, the minimal network is extended and a biologically plausible neuronal population model is developed which considers functional outcome of astrocyte-neuron interactions too. The employed structure is based on the physiological and anatomical network properties of the hippocampal CA1 area. Utilizing these two different levels of modeling, it is demonstrated that astrocytes are able to change the threshold value of transition from synchronous to asynchronous behavior among neurons. In this way, variations in the interaction between astrocytes and neurons lead to the emergence of synchronous/asynchronous patterns in neural responses. Furthermore, population spikes are recorded from CA1 pyramidal neurons in rat hippocampal slices to validate the modeling results. It demonstrates that astrocytes play a primary role in neuronal firing synchronicity and synaptic coordination. These results may offer a new insight into understanding the mechanism by which astrocytes contribute to stabilizing neural activities.