Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats.

BACKGROUND: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 µg/0.5 µL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. RESULTS: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 µg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. CONCLUSIONS: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

Activation of medial orbitofrontal cortex abolishes fear extinction and interferes with fear expression in rats.

Pavlovian fear conditioning and extinction procedures have long been used to study the regulation of learned fear. The amygdala is vital for the association of cues and fear expression, whereas the medial prefrontal cortex (mPFC) is critical for fear regulation after extinction. The medial orbitofrontal cortex (mOFC) has an extensive connection with the fear circuit. In human studies, emotional regulation disorders, such as obsessive-compulsive disorder and post-traumatic stress disorder, are often linked to an abnormality in the orbitofrontal cortex (OFC). Therefore, in a series of experiments, we examined whether abnormal mOFC activities interfere with the regulation of learned fear. The mOFC of rats was pharmacologically activated with N-methyl-D-aspartate (NMDA) during the acquisition, early consolidation, or retrieval phase of fear extinction. Under mOFC activation, there was a general initial suppression of the fear response followed by the development of nonspecific fear expression. Moreover, pre-extinction activation of the mOFC abolished extinction acquisition, causing an up-shift in the fear response during the retrieval test. Nonetheless, immediate post-extinction activation of the mOFC did not interfere with extinction consolidation. Overall, our results suggested that mOFC activation abolished fear extinction acquisition and interfered with fear expression.

Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke.

Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.

Effects of glutamate-related drugs on anxiety and compulsive behavior in rats with obsessive-compulsive disorder.

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). We examined the effects and potential mechanism of glutamate-related drugs on compulsive behavior in quinpirole (QNP)-sensitized rats, to deepen our understanding of the link between OCD and glutamate.Method: This study systematically compared the effects of the partial NMDA agonist D-Cycloserine and the NMDA antagonist NVP-AAMO77, Ro25-6981 on compulsive behavior using the elevated zero maze, open field, and marble burying tests in QNP-induced OCD model.Results: The competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists NVP-AAMO77 (5 mg/kg) and Ro25-6981 (5 mg/kg) significantly inhibited anxiety-like and compulsive behavior in rats. And D-Cycloserine at all doses showed significant suppression on anxiety-like and marble-burying behavior. Glutamic acid (Glu) levels, reflecting changes in the glutamatergic neurotransmission, were significantly decreased in rat hippocampus of the NVP-AAMO77 and D-Cycloserine-treated group compared to the saline-treated group. The levels of other amino acids were unaffected. Moreover, NVP-AAMO77 significantly decreased the expression of the subunit NR2A of the NMDAR, and Ro25-6981 suppressed the level of the subunit NR2B of the NMDAR, while D-Cycloserine decreased both the subunit NR2A and NR2B of the NMDAR.Conclusion: Collectively, these findings suggest a functional role of NMDARs in anxiety and compulsive behaviors, with NMDARs inhibition promoting anxiolytic-like and anti-compulsive responses. These findings suggest that D-cycloserine, NVP-AAMO77, and Ro25-6981 could be useful drugs for the treatment of OCD, which may be due to the suppression of NR2A- or NR2B- containing NMDAR.

Convergent Inputs from the Hippocampus and Thalamus to the Nucleus Accumbens Regulate Dopamine Neuron Activity.

Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. The pathway by which the ventral hippocampus (vHipp) regulates dopamine neuron activity has been demonstrated previously and involves a glutamatergic projection to the nucleus accumbens (NAc). Recent postmortem studies have confirmed glutamatergic abnormalities in the NAc of individuals with schizophrenia. Specifically, an increase in vesicular glutamate transporter 2 (vGlut2) expression was reported. Although projections from the hippocampus do express vGlut2, inputs from the thalamus are more likely to account for this alteration; however, the role of thalamic inputs to the NAc in the regulation of dopamine neuron activity has not been elucidated. Here, using male Sprague Dawley rats, we demonstrate that a subset of NAc medium spiny neurons receive convergent inputs from the vHipp and paraventricular nucleus of the thalamus (PVT), with both regions working synergistically to regulate dopamine neuron activity. Activation of either the vHipp or PVT increases the number of spontaneously active dopamine neurons in the ventral tegmental area. Moreover, this regulation requires simultaneous activity in both regions because PVT inactivation can reverse vHipp-induced increases in dopamine neuron population activity and vHipp inactivation can reverse PVT-induced increases. This is relevant to schizophrenia because inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in two distinct rodent models. These data suggest that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and that the PVT represents a novel site of intervention for psychosis.SIGNIFICANCE STATEMENT Current treatments for schizophrenia are far from adequate and a more complete understanding of the pathophysiology underlying this disease is warranted if we are to discover novel therapeutic targets. We have previously demonstrated that the aberrant dopamine system function observed in individuals with schizophrenia and rodent models is driven by increases in hippocampal activity. We now demonstrate that thalamic (paraventricular nucleus, PVT) and ventral hippocampal afferents converge in the nucleus accumbens to regulate dopamine system function. Such information provides a potential site for therapeutic intervention for schizophrenia. Indeed, inactivation of the PVT can effectively reverse aberrant dopamine system function in two distinct rodent models displaying circuit level alterations and corresponding behavioral deficits relevant to schizophrenia.

Specific inter-stimulus interval effect of NMDA receptor activation in the insular cortex during conditioned taste aversion.

Taste memory recognition is crucial for species survival; thus, the acquisition of conditioned taste aversion (CTA) protects animals against consuming poisons or toxins. In nature, food and poison are confined in the same edible item; however, in the laboratory these food constituents are usually presented separately for experimental analysis. The taste, or conditioned stimulus (CS), can be hours apart from the gastric malaise, or unconditioned stimulus (US); this extended inter-stimulus interval (ISI) allows the analysis of a particular learning phase. Evidence indicates a relevant function of glutamatergic activity in the insular cortex (IC) throughout the ISI. N-methyl-D-aspartate receptors (NMDAR) are crucial during CTA acquisition and retrieval. However, the exact participation of NMDAR in the IC during the ISI has not been demonstrated. Thus, the aim of this work was to evaluate the effects of temporal NMDAR activation during four time frames throughout the ISI of conditioned sugar aversion with bilateral injections of NMDA at a physiological dose (1 µg/µl) in the IC, given (1) immediately before or (2) immediately after sugar presentation, or (3) immediately before or (4) immediately after LiCl i.p. injection. The results showed that NMDAR activation in the IC had a specific ISI effect during CTA acquisition, increasing aversive memory formation and delaying extinction only after CS presentation. Overall, these results demonstrate that NMDAR in the IC have a particular enhancing associative effect after CS and suggest that there is a precise coincidence in neurochemical events in the IC that correlates with the stimulus to be associated and the glutamate NMDAR activity that must be finely tuned in the ISI during CTA acquisition.

Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity.

Epileptic seizures are associated with increased astrocytic Ca2+ signaling, but the fine spatiotemporal kinetics of the ictal astrocyte-neuron interplay remains elusive. By using 2-photon imaging of awake head-fixed mice with chronic hippocampal windows we demonstrate that astrocytic Ca2+ signals precede neuronal Ca2+ elevations during the initial bout of kainate-induced seizures. On average, astrocytic Ca2+ elevations preceded neuronal activity in CA1 by about 8 s. In subsequent bouts of epileptic seizures, astrocytes and neurons were activated simultaneously. The initial astrocytic Ca2+ elevation was abolished in mice lacking the type 2 inositol-1,4,5-trisphosphate-receptor (Itpr2-/-). Furthermore, we found that Itpr2-/- mice exhibited 60% less epileptiform activity compared with wild-type mice when assessed by telemetric EEG monitoring. In both genotypes we also demonstrate that spreading depression waves may play a part in seizure termination. Our findings imply a role for astrocytic Ca2+ signals in ictogenesis.

Modulation of NMDA-mediated intrinsic membrane properties of ascending commissural interneurons in neonatal rat spinal cord.

In this paper, the modulation of ascending commissural interneurons by N-methyl-D-aspartate was investigated in neonatal rats by using retrograde labeling and whole-cell patch clamp. Data shows these interneurons can be divided into three types (single spike, phasic, and tonic) based on their firing patterns. A hyperpolarization-activated nonselective cation current and persistent inward current are expressed in these interneurons. The parameters studied (n = 48) include: resting membrane potential (-59.2 ± 0.8 mV), input resistance (964.4 ± 49.3 MΩ), voltage threshold (-39.5 ± 0.6 mV), rheobase (13.5 ± 0.7 pA), action potential height (55.6 ± 2.2 mV), action potential half-width (2.8 ± 0.1 ms), afterhyperpolarization magnitude (16.1 ± 1.2 mV) and half-decay (217.9 ± 10.7 ms). 10 µM N-methyl-D-aspartate increases excitability of ascending commissural interneurons by depolarizing the membrane potential, hyperpolarizing voltage threshold, reducing rheobase, and shifting the frequency-current relationship to the left. N-methyl-Daspartate enhances persistent inward currents but reduces hyperpolarization-activated nonselective cation currents. This research uncovers unique ionic and intrinsic properties of ascending commissural interneurons which can be modulated by major excitatory neurotransmitters such as N-methyl-D-aspartate to potentially facilitate left-right alternation during locomotion.

Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice.

Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25-0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug-drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.

Rapid recovery and altered neurochemical dependence of locomotor central pattern generation following lumbar neonatal spinal cord injury.

KEY POINTS: Spinal compression injury targeted to the neonatal upper lumbar spinal cord, the region of highest hindlimb locomotor rhythmogenicity, leads to an initial paralysis of the hindlimbs. Behavioural recovery is evident within a few days and approaches normal function within about 3 weeks. Fictive locomotion in the isolated injured spinal cord cannot be elicited by a neurochemical cocktail containing NMDA, dopamine and serotonin 1 day post-injury, but can 3 days post-injury as readily as in the uninjured spinal cord. Low frequency coordinated rhythmic activity can be elicited in the isolated uninjured spinal cord by NMDA + dopamine (without serotonin), but not in the isolated injured spinal cord. In both the injured and uninjured spinal cord, eliciting bona fide fictive locomotion requires the additional presence of serotonin. ABSTRACT: Following incomplete compression injury in the thoracic spinal cord of neonatal mice 1 day after birth (P1), we previously reported that virtually normal hindlimb locomotor function is recovered within about 3 weeks despite substantial permanent thoracic tissue loss. Here, we asked whether similar recovery occurs following lumbar injury that impacts more directly on the locomotor central pattern generator (CPG). As in thoracic injuries, lumbar injuries caused about 90% neuronal loss at the injury site and increased serotonergic innervation below the injury. Motor recovery was slower after lumbar than thoracic injury, but virtually normal function was attained by P25 in both cases. Locomotor CPG status was tested by eliciting fictive locomotion in isolated spinal cords using a widely used neurochemical cocktail (NMDA, dopamine, serotonin). No fictive locomotion could be elicited 1 day post-injury, but could within 3 days post-injury as readily as in age-matched uninjured control spinal cords. Burst patterning and coordination were largely similar in injured and control spinal cords but there were differences. Notably, in both groups there were two main locomotor frequencies, but injured spinal cords exhibited a shift towards the higher frequency. Injury also altered the neurochemical dependence of locomotor CPG output, such that injured spinal cords, unlike control spinal cords, were incapable of generating low frequency rhythmic coordinated activity in the presence of NMDA and dopamine alone. Thus, the neonatal spinal cord also exhibits remarkable functional recovery after lumbar injuries, but the neurochemical sensitivity of locomotor circuitry is modified in the process.

Disposition of ß-N-methylamino-l-alanine (L-BMAA), a neurotoxin, in rodents following a single or repeated oral exposure.

ß-N-methylamino-l-alanine (L-BMAA) is produced by cyanobacteria (blue-green algae). Human exposure to L-BMAA occurs via consumption of L-BMAA-contaminated water and food. It is speculated that exposure to L-BMAA, and subsequent brain accumulation, may contribute to an increased incidence of neurodegenerative diseases indicating the need to evaluate risk of L-BMAA exposure to humans. As an initial step in this process, we have evaluated disposition following a single or repeated gavage administration of 1, 10 or 100mg/kg [14C]L-BMAA in rats and mice. L-BMAA was well absorbed following a single gavage administration with minimal dose, species, or sex-related effect. In both species, the main excretion route was as exhaled CO2 (46-61%) with 7-13% and 1.4-8% of the administered dose excreted in the urine and feces, respectively. L-BMAA was distributed to all tissues examined; the total radioactivity in tissues increased with the dose and was significant in both species (8-20%). In male rats, L-BMAA was slowly eliminated from blood and tissues (half-lives ≥48h). Following 1, 5 and 10days of dosing in male rats, levels in tissues increased with the number of doses demonstrating potential for accumulation of BMAA-derived equivalents. There was no greater affinity for accumulation in the brain compared to other organs and tissues. Following repeated exposure in rats, amino acid mass shifts associated with L-BMAA were detected in brain peptides. However, the low frequency of occurrence suggests that the substitution of an amino acid with L-BMAA is not significant relative to substitutions and/or modifications by other L-BMAA-derived equivalents.

Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model.

OBJECTIVE: We previously demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate subtype 2 (mGlu2 ) receptors have potential synergistic interactions with the antiseizure drug levetiracetam (LEV). The present study utilizes isobolographic analysis to evaluate the combined administration of JNJ-46356479, a selective and potent mGlu2 PAM, with LEV as well as sodium valproate (VPA) and lamotrigine (LTG). METHODS: The anticonvulsant efficacy of JNJ-46356479 was evaluated in the 6-Hz model of psychomotor seizures in mice. JNJ-46356479 was administered in combination with LEV using 3 fixed dose-ratio treatment groups in the mouse 6-Hz (44-mA) seizure test. The combination of JNJ-46356479 with LEV was also evaluated in the mouse corneal kindling model. The potential interactions of JNJ-46356479 with the antiseizure drugs VPA and LTG were also evaluated using fixed dose-ratio combinations. Plasma levels were obtained for analysis of potential pharmacokinetic interactions for each combination studied in the mouse 6-Hz model. RESULTS: JNJ-46356479 was active in the 6-Hz model at both 32-mA and 44-mA stimulus intensities (median effective dose = 2.8 and 10.2 mg/kg, respectively). Using 1:1, 1:3, and 3:1 fixed dose-ratio combinations (LEV:JNJ-46356479), coadministration was significantly more potent than predicted for additive effects, and plasma levels suggest this synergism was not due to pharmacokinetic interactions. Studies in kindled mice further demonstrate the positive pharmacodynamic interaction of LEV with JNJ-46356479. Using 1:1 dose-ratio combinations of JNJ-46356479 with either VPA or LTG, there were no significant differences observed for coadministration. SIGNIFICANCE: These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu2 PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.

Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex.

The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kölliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 ± 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I-pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation.NEW & NOTEWORTHY A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons.

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target.

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI.

Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine.

Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance. Here we examined underlying neural mechanisms of auditory plasticity deficits using combined behavioural and neurophysiological assessment, along with neuropharmacological manipulation targeted at the N-methyl-D-aspartate type glutamate receptor (NMDAR). Cortical plasticity was assessed in a cohort of 40 schizophrenia/schizoaffective patients relative to 42 healthy control subjects using a fixed reference tone auditory plasticity task. In a second cohort (n = 21 schizophrenia/schizoaffective patients, n = 13 healthy controls), event-related potential and event-related time-frequency measures of auditory dysfunction were assessed during administration of the NMDAR agonist d-serine. Mismatch negativity was used as a functional read-out of auditory-level function. Clinical trials registration numbers were NCT01474395/NCT02156908 Schizophrenia/schizoaffective patients showed significantly reduced auditory plasticity versus healthy controls (P = 0.001) that correlated with measures of cognitive, occupational and social dysfunction. In event-related potential/time-frequency analyses, patients showed highly significant reductions in sensory N1 that reflected underlying impairments in θ responses (P < 0.001), along with reduced θ and ß-power modulation during retention and motor-preparation intervals. Repeated administration of d-serine led to intercorrelated improvements in (i) auditory plasticity (P < 0.001); (ii) θ-frequency response (P < 0.05); and (iii) mismatch negativity generation to trained versus untrained tones (P = 0.02). Schizophrenia/schizoaffective patients show highly significant deficits in auditory plasticity that contribute to cognitive, occupational and social dysfunction. d-serine studies suggest first that NMDAR dysfunction may contribute to underlying cortical plasticity deficits and, second, that repeated NMDAR agonist administration may enhance cortical plasticity in schizophrenia.

Regulation of blood glucose level by kainic acid in mice: involvement of glucocorticoid system and non-NMDA receptors.

Kainic acid (KA) is a well-known excitatory neurotoxic substance. In the present study, effects of KA-injected intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level were investigated in ICR mice. We found that KA administered intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) increased the blood glucose and corticosterone levels, suggesting that KA-induced hyperglycemia appeared to be due to increased blood corticosterone level. In support of this finding, adrenalectomy causes a reduction of KA-induced hyperglycemia and neuronal cell death in CA3 regions of the hippocampus. In addition, pretreatment with i.c.v. or i.t. injection of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione; a non-NMDA receptor blocker) attenuated the i.p. and i.c.v. administered KA-induced hyperglycemia. KA administered i.c.v. caused an elevation of the blood corticosterone level whereas the plasma insulin level was reduced. Moreover, i.c.v. pretreatment with CNQX inhibited the decrease of plasma insulin level induced by KA i.c.v. injection, whereas the KA-induced plasma corticosterone level was further enhanced by CNQX pretreatment. Our results suggest that KA administered systemically or centrally produces hyperglycemia. A glucocorticoid system appears to be involved in KA-induced hyperglycemia. Furthermore, central non-N-methyl-D-aspartate receptors may be responsible for KA-induced hyperglycemia.

Loss-of-function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N-methyl-D-aspartate.

Convincing data demonstrate that D-serine, a racemized product of serine racemase (SR), contributes to neurotoxicity. Furthermore, a line of evidence suggests that SR/D-serine contributes to retinal neurodegeneration in a diabetic retinopathy rat model and diabetic retinopathy patients. However, the connection between SR/D-serine and retinal neurodegeneration remains unclear. Herein, we report that intravitreal injection of N-methyl-D-aspartate (NMDA) induces excitotoxicity in rodent retina; this retinal neurodegeneration was attenuated in retina carrying a loss-of-function of mutation in Srr, the gene for SR, termed Srr(ochre269). Under the condition of NMDA injection, either posterior pole or middle - but not peripheral - retina from Srr(ochre269) mice was found to retain more retinal ganglion cells (RGC) than the counterpart from w/t (RGCs were identified with retrograde labeling). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining further demonstrated reduced RGC apoptosis from Srr(ochre269) compared to w/t mice under the condition of NMDA injection. Collectively, our studies demonstrate a pivotal role of SR/D-serine in retinal neurotoxicity. We demonstrated that loss-of-function mutation of the gene encoding serine racemase significantly attenuates excitotoxicity in retina; excitotoxicity accounts for retinal ganglion cell (RGC) demise in diabetic retinopathy (DR). We think that our findings deepen the current knowledge of the mechanisms of RGC degeneration.

Hippocampal noradrenergic activation is necessary for object recognition memory consolidation and can promote BDNF increase and memory persistence.

Previously we showed that activation of the Nucleus of the Solitary Tract (NTS)-Nucleus Paragigantocellularis (PGi)-Locus coeruleus (LC) pathway, which theoretically culminates with norepinephrine (NE) release in dorsal hippocampus (CA1 region) and basolateral amygdala (BLA) is necessary for the consolidation of object recognition (OR) memory. Here we show that, while the microinjection of the beta-noradrenergic receptor blocker timolol into CA1 impairs OR memory consolidation, the microinjection of norepinephrine (NE) promotes the persistence of this type of memory. Further, we show that OR consolidation is attended by an increase of norepinephrine (NE) levels and of the expression of brain derived neurotrophic factor (BDNF) in hippocampus, which are impaired by inactivation of the NTS-PGi-LC pathway by the infusion of muscimol into the NTS.

Cardiac N-methyl D-aspartate Receptors as a Pharmacological Target.

This study focuses on characterization of the cardiac N-methyl D-aspartate receptors (NMDARs) as a target for endogenous and synthetic agonists and antagonists. Using isolated perfused rat hearts, we have shown that intracoronary administration of the NMDAR agonists and antagonists has a pronounced effect on autonomous heart function. Perfusion of rat hearts with autologous blood supplemented with NMDAR agonists was associated with induction of tachycardia, sinus arrhythmia, and ischemia occurring within physiological plasma concentration range for glutamate and glycine. Intracoronary administration of the NMDAR antagonists exerted an antiarrhythmic effect and resulted in bradycardia and improvement of capillary perfusion. Action of antagonists eliprodil, Ro25-6981, memantine, ketamine, and MK-801 on autonomous heart function diverged strikingly from that of L-type Ca channel blockers. Cardiac NMDAR subunit composition differed from that of neuronal receptors and was age specific and chamber specific. Transcripts of the GluN3A and GluN2D were found in all heart chambers, whereas expression of GluN1 and GluN2A and 2C was restricted to the atria. Expression of the GluN2B protein in ventricles increased markedly with age of the animals. The obtained data reveal that NMDARs are expressed in rat heart contributing to the autonomic heart rate regulation and the function of the cardiac conduction system.