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.

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.

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.

Maladaptive plasticity induced by morphine is mediated by hippocampal astrocytic Connexin-43.

AIMS: Drug addiction is an aberrant learning process that involves the recruitment of memory systems. We have previously demonstrated that morphine exposure causes maladaptive synaptic plasticity which involved hippocampal glial cells, especially astrocytes. Morphine addiction has been associated with astrocytic connexin 43 (Cx43), which plays a role in synaptic homeostasis. This study aimed to examine the role of hippocampal astrocytic Cx43 in morphine-induced maladaptive plasticity as a mechanism of addiction. MAIN METHODS: Male rats were injected with morphine (10 mg/kg) subcutaneously every 12 h for nine days to induce dependence. Cx43 was inhibited by TAT-Gap19 (1 µl/1 nmol) microinjection in the CA1 region of the hippocampus 30 min before each morning morphine injection. Field potential recordings were used to assess synaptic plasticity. fEPSP was recorded from the CA1 area following CA3 stimulation. KEY FINDINGS: Electrophysiological results showed that morphine treatment altered baseline synaptic responses. It also appears that morphine treatment augmented long-term potentiation (LTP) compared with the control group. Hippocampal astrocytic Cx43 inhibition, with the TAT-Gap19, undermines these effects of morphine on baseline synaptic responses and LTP. Despite this, long-term depression (LTD) did not differ significantly between the groups. Additionally, in the morphine-receiving group, inhibition of Cx43 significantly reduced the paired-pulse index at an 80-millisecond inter-pulse interval when assessing short-term plasticity. SIGNIFICANCE: The results of this study demonstrated that inhibiting Cx43 reduced synaptic plasticity induced by morphine. It can be concluded that hippocampal astrocytes through Cx43 are involved in morphine-induced metaplasticity.

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.

Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid.

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD. Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats. Microinjection of TGN-020 (10 µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats. Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats. The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring.

Physical or psychological stress experienced by a mother during gestation is often associated with serious behavioural and cognitive deficits in newborns. Investigations of protective agents, which could prevent the adverse outcomes of prenatal stress (PS), are warranted. Agmatine is a neurotransmitter putatively involved in the physiological response to stress, and exogenous administration of agmatine has been shown to produce a variety of neuroprotective effects. In this study, we aimed to assess whether prenatal agmatine exposure could ameliorate behavioural and cognitive deficits in female offspring born to prenatally stressed mice. Pregnant Swiss Webster (SW) mice were exposed to physical or psychological stress from the 11th to 17th days of gestation. Agmatine (37.5 mg/kg, i.p.) was administrated 30 min before the induction of stress for seven consecutive days. The pups were assessed using a variety of behavioural tests and molecular assays on postnatal days 40 to 47. Agmatine attenuated impairments in locomotor activity, anxiety-like behaviour, and drug-seeking behaviour associated with both physical and psychological PS. Furthermore, agmatine reduced PS-induced impairments in passive avoidance memory and learning. Neither PS nor agmatine treatment affected the mRNA expression level of hippocampal brain-derived neurotrophic factor (BDNF) or tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). Taken together, our findings highlight the protective effects of prenatally administered agmatine on PS-mediated behavioural and cognitive deficits of the offspring. Future studies are needed to elucidate the underlying mechanisms, which could allow for more targeted prenatal treatments.

Glycolysis inhibition partially resets epilepsy-induced alterations in the dorsal hippocampus-basolateral amygdala circuit involved in anxiety-like behavior.

Pharmacoresistant temporal lobe epilepsy affects millions of people around the world with uncontrolled seizures and comorbidities, like anxiety, being the most problematic aspects calling for novel therapies. The intrahippocampal kainic acid model of temporal lobe epilepsy is an appropriate rodent model to evaluate the effects of novel interventions, including glycolysis inhibition, on epilepsy-induced alterations. Here, we investigated kainic acid-induced changes in the dorsal hippocampus (dHPC) and basolateral amygdala (BLA) circuit and the efficiency of a glycolysis inhibitor, 2-deoxy D-glucose (2-DG), in resetting such alterations using simultaneous local field potentials (LFP) recording and elevated zero-maze test. dHPC theta and gamma powers were lower in epileptic groups, both in the baseline and anxiogenic conditions. BLA theta power was higher in baseline condition while it was lower in anxiogenic condition in epileptic animals and 2-DG could reverse it. dHPC-BLA coherence was altered only in anxiogenic condition and 2-DG could reverse it only in gamma frequency. This coherence was significantly correlated with the time in which the animals exposed themselves to the anxiogenic condition. Further, theta-gamma phase-locking was lower in epileptic groups in the dHPC-BLA circuit and 2-DG could considerably increase it.

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.

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.

Perspectives on Agmatine Neurotransmission in Acute and Chronic Stressrelated Conditions.

Adaptive responses to stressful stimuli in the environment are believed to restore homeostasis after stressful events. Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases glucocorticoids (GCs) into the bloodstream. Recently, agmatine, an endogenous monoamine was discovered to have the potential as a pharmacotherapy for stress. Agmatine is released in response to certain stress conditions, especially those involving GCs, and participates in establishing homeostasis disturbed by stress following GC activation. The therapeutic potential of agmatine for the management of psychological diseases involving stress and depression is promising based on a significant amount of literature. When exogenously applied, agmatine leads to reductions in levels of GCs and counteracts stress-related morphologic, synaptic, and molecular changes. However, the exact mechanism of action by which agmatine modifies the effects resulting from stress hormone secretion is not fully understood. This review aims to present the most possible mechanisms by which agmatine reduces the harmful effects of chronic and acute stress. Several studies suggest chronic stress exposure and repeated corticosteroid treatment lower agmatine levels, contributing to stress-related symptoms. Agmatine acts as an antistress agent by activating mTOR signaling, inhibiting NMDA receptors, suppressing iNOS, and maintaining bodyweight by activating α-2adrenergic receptors. Exogenous administration that restores agmatine levels may provide protection against stress-induced changes by reducing GCs release, stimulating anti-inflammatory processes, and releasing neuroprotective factors, which are not found in all therapies currently being used to treat stress-related disorders. The administration of exogenous agmatine should also be considered a therapeutic element that is capable of triggering a neural protective response that counters the effects of chronic stress. When combined with existing treatment strategies, this may have synergistic beneficial effects.

Role of amyloid beta (25-35) neurotoxicity in the ferroptosis and necroptosis as modalities of regulated cell death in Alzheimer's disease.

Neuronal cell death as a prominent pathological feature contributes to cognitive decline and memory loss in Alzheimer's disease. We investigated the role of two forms of cell death pathways, ferroptosis and necroptosis, and their interactions following entorhinal cortex (EC) amyloidopathy. The Aß25-35 was bilaterally injected into the rat's EC, and Morris Water Maze was applied to determine spatial performance one week after Aß injection. For evaluation of ferroptosis and necroptosis involvement in Aß induced pathology, ferroptosis inhibitor, Ferrostatin (Fer-1), and necroptosis inhibitor, Necrostatin (Nec-1), were injected into the EC during training days of behavioral test. Our behavioral and histological assessment showed spatial learning and memory impairment, along with neuropathology changes such as cell survival and intracellular Aß deposits in response to EC amyloidopathy, which were ameliorated by treatment with Fer-1 or Nec-1. The expression of ferroptosis key factors GPX4 and SLC7A11 were decreased and the level of TfR was increased following Aß toxicity. Also, Necroptosis pathway related factors RIP1, RIP3, and MLKL were modulated by Aß neurotoxicity. However, application of Fer-1 or Nec-1 could inhibit the hippocampal ferroptosis and necroptosis pathways due to EC amyloidopathy. Our data also demonstrated that Aß-induced necroptosis suppressed by Fer-1, although Nec-1 had no effect on ferroptosis, indicating that ferroptosis pathway is upstream of necroptosis process in the Aß neurotoxicity. Moreover, Aß induced hippocampal mGLUR5 overexpression and reduced level of STIM1/2 recovered by Fer-1 or Nec-1. According to our findings ferroptosis and necroptosis pathways are involved in Aß neurotoxicity through modulation of mGLUR5 and STIM1/2 signaling.

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.

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.

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.

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.

Involvement of Hippocampal Astrocytic Connexin-43 in Morphine dependence.

Repeated exposure to drugs of abuse can lead to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters. Such alterations in neurotransmission modify synaptic plasticity which causes addictive-like behaviors. Our previous study shed light on the involvement of glial cells in morphine-induced behavioral responses. It has been shown that glial cells play an indispensable role in synaptic transmission through the release of gliotransmitter into and uptake of neurotransmitters from the synaptic cleft. Connexin-43 (Cx43), the dominant Cx protein in astrocytes, is the main component of astrocytic gap junctions and hemichannels. It has a critical role in synaptic efficacy through setting the amount of presynaptic gliotransmitter release in physiological conditions. It is probable that addictive substances affecting gliotransmitters release through the alteration of Cx43 function. In this study, we examined the role of the hippocampal-specific astrocytic connexin (Cx43) in morphine-induced behavioral responses. Male rats received subcutaneous (s.c.) morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. The animals received microinjection of TAT-Gap19 (inhibitor of Cx43) into the CA1 region before each morning morphine administration. The animals were assessed for morphine dependence by monitoring naloxone hydrochloride precipitated withdrawal somatic signs. Results showed that animals receiving TAT-Gap19 before morphine injection demonstrated a significant reduction in several signs of morphine withdrawal such as Activity, Freezing, Chewing, Ptosis, Defecation, Teeth chattering, Writhing, Penis- licking, Head tremor, Scratching, Sniffing, Rearing, and Diarrhea (One way ANOVA, P < 0.001; P < 0.01; P < 0.05). Our findings suggest that hippocampal Cx43 may be involved in morphine-induced behavioral responses. Therefore, gliotransmitter release by astrocytes seems to be a mechanism which is engaged in addictive-like behaviors.

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.