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• DKK1 infusion into the CA1 impaired the reconsolidation of contextual fear memory. • SFRP1 infusion into the CA1 had no effect on reconsolidation of contextual fear memory. • Wnt/β-catenin is necessary for CFC memory reconsolidation up to 2 h after reactivation. • There is a link between Wnt/β-catenin and NMDA receptors on CFC memory reconsolidation. Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/β-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/β-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/β-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/β-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Arsenic results in synaptic plasticity impairment of hippocampal neurons. • NMDARs mediate synaptic plasticity impairment due to arsenic exposure. • Arsenic affects NMDARs in diverse ways. Endemic arsenism is a worldwide health problem. Chronic arsenic exposure results in cognitive dysfunction due to arsenic and its metabolites accumulating in hippocampus. As the cellular basis of cognition, synaptic plasticity is pivotal in arsenic-induced cognitive dysfunction. N-methyl-D-aspartate receptors (NMDARs) serve physiological functions in synaptic transmission. However, excessive NMDARs activity contributes to exitotoxicity and synaptic plasticity impairment. Here, we provide an overview of the mechanisms that NMDARs and their downstream signaling pathways mediate synaptic plasticity impairment due to arsenic exposure in hippocampal neurons, ways of arsenic exerting on NMDARs, as well as the potential therapeutic targets except for water improvement. [ABSTRACT FROM AUTHOR]

• Here, we estimate the effects of acetylcholine (ACh) on CA3 synaptic integration. • Higher input resistance in distal dendrites reduces the NMDA spike threshold. • ACh broadly reduces the number of synapses needed to trigger NMDA spikes. • The magnitude of the effect varies across dendrite branches within a single neuron. • No single potassium channel type is the dominant mediator of the effects of ACh. Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles. [ABSTRACT FROM AUTHOR]

• Subanesthetic ketamine induces short-term hyperlocomotion. CBD pretreatment prolonged this motor effect. • Subanesthetic ketamine decreases NR1 and NR2B NMDA subunit expression and ERK phosphorylation state in the NAc. • CBD pretreatment exerts opposite effects in NR1, NR2B levels and ERK phosphorylation in NAc compared to ketamine per se. • Subanesthetic ketamine decreases NR2B levels in the ventral hippocampus. CBD pretreatment reverses this effect. Cannabidiol (CBD) is a non-addictive ingredient of cannabis with antipsychotic potential, while ketamine (KET), an uncompetitive NMDA receptor inhibitor, has been extensively used as a psychotomimetic. Only few studies have focused on the role of CBD on the KET-induced motor profile, while no study has investigated the impact of CBD on KET-induced alterations in NMDA receptor subunit expression and ERK phosphorylation state, in brain regions related to the neurobiology and treatment of schizophrenia. Therefore, the aim of the present study is to evaluate the role of CBD on KET-induced motor response and relevant glutamatergic signaling in the prefrontal cortex, the nucleus accumbens, the dorsal and ventral hippocampus. The present study demonstrated that CBD pre-administration did not reverse KET-induced short-lasting hyperactivity, but it prolonged it over time. CBD alone decreased motor activity at the highest dose tested (30 mg/kg) while KET increased motor activity at the higher doses (30, 60 mg/kg). Moreover, KET induced regionally-dependent alterations in NR1 and NR2B expression and ERK phosphorylation that were reversed by CBD pre-administration. Interestingly, in the nucleus accumbens KET per se reduced NR2B and p-ERK levels, while the CBD/KET combination increased NR2B and p-ERK levels, as compared to control. This study is the first to show that CBD prolongs KET-induced motor stimulation and restores KET-induced effects on glutamatergic signaling and neuroplasticity-related markers. These findings contribute to the understanding of CBD effects on the behavioral and neurobiological profiles of psychotogenic KET. [ABSTRACT FROM AUTHOR]

Highlights • Adolescent stress increases anxiety-like behaviors. • Anxiety-like behaviors decrease from adolescence to adulthood in control animals. • Adolescent stress impacts the prefrontal cortex in a sex- and age-specific manner. • Parvalbumin cell counts correlate with anxiety behavior in adult control females. Abstract Adolescence is a window of vulnerability to environmental factors such as chronic stress that can disrupt brain development and cause long-lasting behavioral dysfunction, as seen in disorders like depression, anxiety, and schizophrenia. There are also sex differences in the prevalence of these disorders across the lifespan. However, the mechanisms of how adolescent stress contributes to neuropsychiatric phenotypes are not well understood, nor are the mediating effects of sex. We hypothesize that adolescent stress disrupts the γ-aminobutyric acid (GABA) system in the prefrontal cortex (PFC) in a sex-specific manner, as this system matures during adolescence and plays an important role in cognitive and emotional functioning. We exposed male and female mice to unpredictable chronic mild stress (UCMS) during adolescence (post-natal day [PND] 28–42). One cohort underwent testing for PFC-related behavioral and molecular changes 24 h following the cessation of stress (late adolescence); a separate cohort was tested approximately 2.5 weeks after the end of UCMS (adulthood). We observed an age-related decline in anxiety-like behaviors in control mice, while mice stressed in adolescence showed elevated anxiety-like behaviors in both adolescence and adulthood. PFC-dependent cognitive functioning was also impaired in adult males stressed in adolescence. Adolescent stress disrupted expression patterns of parvalbumin (PV) and perineuronal nets (PNNs) in the PFC, as well as NMDA receptor subunit composition, in a sex- and age-specific manner. The findings presented here contribute to understanding how adolescent stress may lead to neuropsychiatric disorders such as anxiety by disrupting the development of the PFC and emotional behaviors. [ABSTRACT FROM AUTHOR]

Synchronous, rhythmic firing of GABAergic interneurons is a fundamental mechanism underlying the generation of brain oscillations, and evidence suggests that NMDA receptors (NMDARs) play a key role in oscillatory activity by regulating the activity of interneurons. Consistent with this, derangement of brain rhythms in certain neuropsychiatric disorders, notably schizophrenia and autism, is associated with NMDAR hypofunction and loss of inhibitory interneurons. In the basolateral amygdala (BLA)—dysfunction of which is involved in a host of neuropsychiatric diseases—, principal neurons display spontaneous, rhythmic “bursts” of inhibitory activity, which could potentially be involved in the orchestration of oscillations in the BLA network; here, we investigated the role of NMDARs in these inhibitory oscillations. Rhythmic bursts of spontaneous IPSCs (0.5 Hz average burst frequency) recorded from rat BLA principal cells were blocked or significantly suppressed by D-AP5, and could be driven by NMDAR activation alone. BLA interneurons generated spontaneous bursts of suprathreshold EPSCs at a similar frequency, which were also blocked or reduced by D-AP5. PEAQX (GluN2A-NMDAR antagonist; 0.4 μM) or Ro-25-6981 (GluN2B-NMDAR antagonist; 5 μM) suppressed the IPSC and EPSC bursts; suppression by PEAQX was significantly greater than that by Ro-25-6981. Immunohistochemical labeling revealed the presence of both GluN2A- and GluN2B-NMDARs on GABAergic BLA interneurons, while, functionally, GluN2A-NMDARs have the dominant role, as suggested by a greater reduction of NMDA-evoked currents by PEAQX versus Ro-25-6981. Entrainment of BLA principal neurons in an oscillatory generation of inhibitory activity depends primarily on activation of GluN2A-NMDARs, and interneuronal GluN2A-NMDARs may play a significant role. [ABSTRACT FROM AUTHOR]

The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents. Wistar rats were implanted with local field potential recording electrodes in the prefrontal cortex, dorsal hippocampus and nucleus accumbens, as well as cannulae in these regions to facilitate drug infusion. Rats received bilateral infusions of MK801 (0, 5 μg, 20 μg, 50 μg) into one of the three target regions and their behavior measured in an open field. We also assessed the effects of systemic MK801 injection (0.16 mg/kg sc). Electrophysiological signals were recorded continuously, allowing assessment of gamma oscillations (30–80 Hz) and high-frequency oscillations (HFO: 130–180 Hz) occurring as a result of infusions. Regardless of MK801 infusion location, gamma oscillations and HFOs significantly and consistently increased in all three regions studied, similar to that observed following systemic injection. Locomotor activity, stereotypies and ataxia were also observed following infusion into all regions. We conclude that localized regions exhibiting NMDAr hypofunction are sufficient to disrupt local as well as diffuse neural circuits and global brain function, and concomitantly cause psychosis-related behavioral effects. [ABSTRACT FROM AUTHOR]

During postnatal development, neural circuits are extremely dynamic and develop precise connection patterns that emerge as a result of the elimination of synaptic terminals, a process instructed by molecular cues and patterns of electrical activity. In the rodent visual system, this process begins during the first postnatal week and proceeds during the second and third postnatal weeks as spontaneous retinal activity and finally use-dependent fine tuning takes place. Reelin is a large extracellular matrix glycoprotein able to affect several steps of brain development, from neuronal migration to the maturation of dendritic spines and use-dependent synaptic development. In the present study, we investigated the role of reelin on the topographical refinement of primary sensory connections studying the development of retinal ganglion cell axon terminals in the rat superior colliculus. We found that reelin levels in the visual layers of the superior colliculus are the highest between the second and third postnatal weeks. Blocking reelin signaling with a neutralizing antibody (CR-50) from PND 7 to PND 14 induced a non-specific sprouting of ipsilateral retinocollicular axons outside their typical distribution of discrete patches of axon terminals. Also we found that reelin blockade resulted in reduced levels of phospho-GAP43, increased GluN1 and GluN2B-NMDA subunits and decreased levels of GAD65 content in the visual layers of the superior colliculus. The results suggest that reelin signaling is associated with the maturation of excitatory and inhibitory synaptic machinery influencing the development and fine tuning of topographically organized neural circuits during postnatal development. [ABSTRACT FROM AUTHOR]

l -Glutamate and l -aspartate are the main excitatory amino acids (EAAs) in the Central Nervous System (CNS) and their uptake regulation is critical for the maintenance of the excitatory balance. Excitatory amino acid transporters (EAATs) are widely distributed among central neurons and glial cells. GLAST and GLT1 are expressed in glial cells, whereas excitatory amino acid transporter 3/excitatory amino acid carrier 1 (EAAT3/EAAC1) is neuronal. Different signaling pathways regulate glutamate uptake by modifying the activity and expression of EAATs. In the present work we show that immature postnatal day 3 (PN3) rat retinas challenged by l -glutamate release [ 3 H]- d -Aspartate linked to the reverse transport, with participation of NMDA, but not of non-NMDA receptors. The amount of [ 3 H]- d -Aspartate released by l -glutamate is reduced during retinal development. Moreover, immature retinae at PN3 and PN7, but not PN14, exposed to a single dose of 200 or 500 μM caffeine or the selective A2A receptor (A2AR) antagonist 100 nM ZM241385 decreased [ 3 H]- d -Aspartate uptake. Caffeine also selectively increased total expression of EAAT3 at PN7 and its expression in membrane fractions. However, both EAAT1 and EAAT2 were reduced after caffeine treatment in P2 fraction. Addition of 100 nM DPCPX, an A1 receptor (A1R) antagonist, had no effect on the [ 3 H]- d -Aspartate uptake. [ 3 H]- d -Aspartate release was dependent on both extracellular sodium and D l -TBOA, but not calcium, implying a transporter-mediated mechanism. Our results suggest that in the developing rat retina caffeine modulates [ 3 H]- d -Aspartate uptake by blocking adenosine A2AR. [ABSTRACT FROM AUTHOR]

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N -Methyl- d -aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100 μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005 mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals’ locomotion. Co-administration of sub-effective doses of MK-801 (0.001 mg/kg, i.p.) and capsaicin (10 μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100 μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5 mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors. [ABSTRACT FROM AUTHOR]

The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17 kDa tau45-230 fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau45-230 and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau45-230 mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau45-230 is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ. [ABSTRACT FROM AUTHOR]

Highlights: [•] Noradrenaline modulates NMDA-mediated excitations in vestibular nuclei. [•] Both alpha and beta noradrenergic receptors are involved in this modulation. [•] The enhancing or depressing effects of noradrenaline are due to different receptors. [•] Noradrenergic and NMDA receptors coexist throughout the vestibular complex. [Copyright &y& Elsevier]

Highlights: [•] Kynurenic acid (KYNA) had sedative and hypnotic effects during stress in chicks. [•] KYNA is an endogenous antagonist of both the α7nACh and NMDA receptors. [•] KYNA inhibited NMDA receptor subgroup containing the NR2A and NR2B subunits. [ABSTRACT FROM AUTHOR]

Abstract: d-Cycloserine (DCS), a co-agonist at the N-methyl-D-aspartate (NMDA) receptor, has proven to be an effective adjunct to cognitive behavioral therapies that utilize extinction. This pharmacological-based enhancement of extinction memory has been primarily demonstrated in neuropsychiatric disorders characterized by pathological fear (e.g. posttraumatic stress disorder and various phobias). More recently, there has been an interest in applying such a strategy in the disorders of appetitive learning (e.g. substance abuse and other addictions), but these studies have generated mixed results. Here we first examined whether extinction memory encoding in a sucrose self-administration model is dependent on NMDA receptors. The NMDA antagonist (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (5mg/kg, i.p.) administered 2h prior to the first extinction training session effectively inhibited extinction memory recall 24h later, without affecting the expression of the conditioned sucrose-seeking response while the drug was on board. This profile of effects suggests a specific effect on extinction memory consolidation. Next, we sought to enhance extinction memory using the co-agonist DCS (10μg/side) by infusion directly into infralimbic medial prefrontal cortex, a brain site implicated in extinction memory recall in conditioned fear models. Indeed, infusion of DCS immediately after the first extinction training session effectively enhanced extinction memory recall 24h later. Collectively, these data suggest that the neurobiological mechanisms and the neurocircuitry mediating extinction memory are similar regardless of the valence (aversive or appetitive) of the conditioned behavior, and that similar pharmacological strategies for treatment may be applied to neuropsychiatric disorders characterized by a failure to inhibit pathological emotional memories. [Copyright &y& Elsevier]

Abstract: Children with type 1 diabetes mellitus (DM) are at risk of developing cognitive difficulties. Although a diabetes onset of patient influences cognitive difficulties, synaptic properties related to the age of diabetes onset remain unknown. Here we showed that synaptic plasticity including long-term potentiation (LTP) or long-term depression (LTD), and excitatory synaptic transmission at Schaffer collateral-CA1 (SC-CA1) synapses in hippocampal slices were affected by age of onset in rats with streptozotocin-induced diabetes (STZ-rats), compared with age-matched control rats. LTP was impaired and the ratio of AMPA receptor-mediated EPSCs relative to N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs (the AMPA/NMDA ratio) decreased in young adult-onset STZ-rats, whereas LTD was impaired and both AMPA receptor-mediated and NMDA receptor-mediated EPSCs increased in juvenile-onset STZ-rats. Furthermore, impaired LTD of juvenile-onset STZ-rats was restored with an NMDA receptor antagonist. These results suggest that the pathophysiology of diabetes-induced cognitive difficulties varies with the age of diabetes onset. [Copyright &y& Elsevier]

Abstract: Excitotoxic insults can lead to intracellular signaling cascades that contribute to cell death, in part by activation of proteases, phospholipases, and endonucleases. Cysteine proteases, such as calpains, are calcium (Ca2+)-activated enzymes which degrade cytoskeletal proteins, including microtubule-associated proteins, tubulin, and spectrin, among others. The current study used the organotypic hippocampal slice culture model to examine whether pharmacologic inhibition of cysteine protease activity inhibits N-methyl-D-aspartate- (NMDA-) induced excitotoxic (20μM NMDA) cell death and changes in synaptophysin immunoreactivity. Significant NMDA-induced cytotoxicity (as measured by propidium iodide [PI] uptake) was found in the CA1 region of the hippocampus at all timepoints examined (24, 72, 120h), an effect significantly attenuated by co-exposure to the selective NMDA receptor antagonist DL-2-Amino-5-phosphonopentanoic acid (APV), but not MDL-28170, a potent cysteine protease inhibitor. Results indicated sparing of NMDA-induced loss of the synaptic vesicular protein synaptophysin in all regions of the hippocampus by MDL-28170, though only at early timepoints after injury. These results suggest Ca2+-dependent recruitment of cysteine proteases within 24h of excitotoxic insult, but activation of alternative cellular degrading mechanisms after 24h. Further, these data suggest that synaptophysin may be a substrate for calpains and related proteases. [Copyright &y& Elsevier]

Abstract: Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type-B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals. [Copyright &y& Elsevier]

Abstract: The balance between corticostriatal glutamate inputs and mesostriatal dopamine afferents converging onto the same postsynaptic spines of striatal medium spiny neurons in the dorsal striatum is believed to be crucial for regulating executive functions including attention.In the present study we examined the role of dopamine D1 and glutamate N-methyl-d-aspartate (NMDA) receptors within the medial territory of the dorsal striatum (dm-STR) of the rat during performance of a selective attention task such as the 5-choice serial reaction time (5-CSRT) task, which incorporates a variety of measures including accuracy of visual discrimination (an index of attentional functioning), omissions, premature and perseverative responses (indices of inhibitory response control) and correct response latency (decision time). Infusion of 30 ng/side of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the dm-STR decreased accuracy and increased the proportion of omission but had no effect on premature or perseverative responding or correct response latency. A lower dose of 10 ng/side CPP only affected omissions. Blockade of D1 receptors in the dm-STR by SCH23390 (50 and 100 ng/side) had no effect on accuracy but at 100 ng/side SCH23390 decreased anticipatory responding and increased the proportion of omissions. Co-infusion of SCH23390 (50 ng/side) and CPP (10 ng/side), at individually ineffective doses, potently reduced the accuracy of visual discrimination. The effects were highly selective as no changes in response control, decision time and omissions were detected. The data suggest that the synergistic interaction of D1 and NMDA receptors on the dendritic spines of GABA neurons within the dm-STR may represent a mechanism for the control of attention. [Copyright &y& Elsevier]

Abstract: The lateral nucleus of the amygdala (LA) is a critical structure involved in fear conditioning. We recently showed that regulated exocytosis and endocytosis of postsynaptic A-amino-3-hydroxy-5-methylisoxazole-4-propionate subtype of glutamate receptors (AMPARs) are involved in the expression of N-methyl-d-aspartate subtype glutamate receptors (NMDARs) dependent long-term potentiation (LTP) and long-term depression (LTD) in coronal slices of the LA. However, the molecular mechanisms of this effect remain unclear. In the present study, we investigated the role of distinct NMDAR subtypes in the endocytosis of AMPARs during LTD expression at the synapses of the thalamic inputs to the LA neurons. Here we show that the NMDARs antagonist dl-2-amino-5-phosphonovalerate (D-APV) blocked the induction of LTD and thus prevented endocytosis of surface AMPARs, indicating that NMDAR activation enhanced the internalization of AMPARs in LTD expression. Furthermore, the selective blocking of GluN2B-containing NMDARs completely abolished the NMDAR-induced AMPAR endocytosis, whereas preferential inhibition of GluN2A-containing NMDARs did not block the NMDAR-induced AMPAR endocytosis during LTD expression. These results suggest that there exist a preferred NMDAR subtype for AMPAR internalization and activation of GluN2B-containing NMDARs represent the predominate pathway triggered during the early stages of this NMDAR-induced endocytosis of AMPARs during LTD in the thalamic inputs to the LA of juvenile rats. [ABSTRACT FROM AUTHOR]

Abstract: The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)''s expression in surviving DIV 11 cortical GABAergic neurons in vitro [ Exp Neurol 205:367–382, (2008) Exp Neurol 213:145–153]. An N-methyl-d-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate''s effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate''s effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation and inhibition that is often observed after injury. [Copyright &y& Elsevier]

Abstract: In the present study, both potentiation and depression of the synaptic response were induced in hippocampal CA1 neurons by systematically varying the frequency of low frequency afferent stimulation (LFS) between 0.5 and 25 Hz and the pulse number between 40 and 1000. The input–response relationship for CA1 synapses showed that LFS at a higher frequency or with a smaller pulse number increased the magnitude of potentiation of the synaptic response by increasing the contribution of N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs) to induction of potentiation. One possible mechanism for this bidirectional plasticity was that specific patterns of LFS differentially activate a uniform receptor population in producing depression or potentiation of synaptic responses. However, a pharmacological study indicated that, despite their opposite effects, both the synaptic depression induced by LFS at 1 Hz and the synaptic potentiation induced by LFS at 10 Hz were triggered by co-activation of NMDARs and mGluRs at CA1 synapses. We suggest that activation of protein kinase C or inositol-1,4,5-trisphosphate receptors, both coupled to group 1 mGluRs, is involved in the bidirectional synaptic plasticity induced in hippocampal CA1 neurons by 1–10 Hz LFS. [Copyright &y& Elsevier]

Abstract: Synaptic plasticity plays a crucial role in learning, memory, and cognitive disorders. Cytoskeletal reorganization underlies neuronal synaptic plasticity, but little is known about the regulation of cytoskeletal dynamics in living animals. We used stable isotope labeling to measure the turnover of tubulin in defined microtubule (MT) populations in murine brain. Neuronal MTs generally exhibited low turnover rates in vivo. Basal turnover was highest in tau-associated MTs, intermediate in microtubule-associated protein 2 (MAP2)–associated MTs, and lowest in cold-stable MTs. Labeling of MTs in mature neurons in cell culture yielded similar turnover results. Intracerebroventricular glutamate injection stimulated, via N-methyl-d-aspartic acid receptors, label incorporation (turnover) in cold-stable, tau-associated, and MAP2-associated MTs, the last of which was shown to be dependent on cyclic adenosine-3′, 5′-monophosphorothioate–protein kinase A. Contextual fear conditioning, a hippocampus-mediated form of memory formation, was accompanied by increased turnover of hippocampal MAP2-associated and cold-stable MTs. Treatment with the MT-depolymerizing drug nocodazole reversed the conditioning-induced increase in label incorporation in MAP2-associated MTs, reduced dendritic spine density, and impaired memory formation. The effects of nocodazole on MT turnover were prevented by the MT-stabilizing agent Taxol (Sigma-Aldrich, St. Louis, MO, USA) and by brain-derived nerve growth factor, both of which also restored dendritic spine density and memory formation in this model. In conclusion, these results suggest that changes in hippocampal MT turnover are required for, and are a biomarker of, the synaptic plasticity that is involved in memory formation. [Copyright &y& Elsevier]

Abstract: The development of drug addiction involves persistent cellular and molecular changes in the CNS. The brain dopamine and glutamate systems play key roles in mediating drug-induced neuroadaptation. Changes in dendritic morphology in medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and caudate putamen (CPu) accompany drug-induced enduring behavioral and molecular changes. We have investigated the potential involvement of dopamine D1 and D2 receptors, the N-methyl-d-aspartate (NMDA) receptor, and the extracellular signal-regulated kinase (ERK) in dendritic morphological changes induced by repeated cocaine administration. We show that either a genetic mutation or pharmacological blockade of dopamine D1 receptors attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. In contrast, antagonism of dopamine D2 receptors had no obvious effect on changes in dendritic branching but had a partial effect on changes in spine density of MSNs in these brain regions following repeated cocaine injections. Pharmacological inhibition of either NMDA receptors or ERK attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. These results suggest that dopamine D1 and NMDA receptors and ERK contribute significantly to neuronal morphological changes induced by repeated exposure to cocaine. [Copyright &y& Elsevier]

Abstract: We investigated the effects of the neurosteroid 17β-estradiol (E2) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E2 enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E2. Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic n-methyl-d-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E2 are abolished under D-(−)-2-amino-5-phosphonopentanoic acid (AP-5). E2 also facilitates post-synaptic NMDARs, but it does not affect directly α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E2 modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E2 is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo. [Copyright &y& Elsevier]

Abstract: The first Kavli Prize in Neuroscience recognizes a confluence of career achievements that together provide a fundamental understanding of how brain and spinal cord circuits are assembled during development and function in the adult. The members of the Kavli Neuroscience Prize Committee have decided to reward three scientists (Sten Grillner, Thomas Jessell, and Pasko Rakic) jointly “for discoveries on the developmental and functional logic of neuronal circuits”. Pasko Rakic performed groundbreaking studies of the developing cerebral cortex, including the discovery of how radial glia guide the neuronal migration that establishes cortical layers and for the radial unit hypothesis and its implications for cortical connectivity and evolution. Thomas Jessell discovered molecular principles governing the specification and patterning of different neuron types and the development of their synaptic interconnection into sensorimotor circuits. Sten Grillner elucidated principles of network organization in the vertebrate locomotor central pattern generator, along with its command systems and sensory and higher order control. The discoveries of Rakic, Jessell and Grillner provide a framework for how neurons obtain their identities and ultimate locations, establish appropriate connections with each other, and how the resultant neuronal networks operate. Their work has significantly advanced our understanding of brain development and function and created new opportunities for the treatment of neurological disorders. Each has pioneered an important area of neuroscience research and left a legacy of exceptional scientific achievement, insight, communication, mentoring and leadership. [Copyright &y& Elsevier]

Abstract: Ghrelin induces orexigenic behavior by activation of growth hormone secretagogue 1 receptors (GHSRs) in the ventral tegmental area (VTA) as well as hypothalamus, suggesting the involvement of mesolimbic dopamine system in the action of ghrelin. The present study aimed to identify neuronal mechanisms by which peripherally administered ghrelin regulates the mesolimbic dopamine system under different food-consumptive states. Ghrelin was administered to rats peripherally (3 nmol, i.v.) as well as locally into the VTA (0.3 nmol). Dopamine in the nucleus accumbens shell (NAc) was measured by microdialysis. Peripheral administration of ghrelin decreased dopamine levels in the NAc when food was removed following ghrelin administration. This inhibitory effect was mediated through GABAA and N-methyl-d-aspartate (NMDA) receptors in the VTA. In contrast, when animals consumed food following ghrelin administration, dopamine levels increased robustly. This stimulatory effect was mediated through NMDA receptors, but not through GABAA receptors, in the VTA. Importantly, both the inhibitory and stimulatory effects of ghrelin primarily required activation of GHSRs in the VTA. Furthermore, local injection of ghrelin into the VTA induced dopamine release in the NAc and food consumption, supporting the local action of ghrelin in the VTA. In conclusion, peripherally administered ghrelin activates GHSRs in the VTA, and induces bimodal effects on mesolimbic dopamine neurotransmission depending on food-consumptive states. [Copyright &y& Elsevier]

Abstract: Prenatal exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg) contaminated food may affect brain development, leading to long-term alterations in cognitive function. Both types of contaminants, PCBs and MeHg, are often found together contaminating food, especially fish in some polluted areas. Exposure to combinations of neurotoxicants may exert different effects on the developing nervous system than exposure to individual contaminants. Developmental exposure (during pregnancy and lactation) to PCB126 or PCB153 impairs learning ability when the rats are 3 months old. Impairment of learning seems to be a consequence of impairment of the function of the glutamate–nitric oxide (NO)–cGMP pathway in brain in vivo. The aims of the present work were 1) to assess whether perinatal exposure to MeHg also affects the function of the glutamate–NO–cGMP pathway in brain in vivo analyzed by in vivo brain microdialysis and/or the ability to learn the Y maze task when the rats are 3 months old, and 2) to assess whether perinatal exposure to combinations of MeHg with PCB153 or PCB126 potentiates, decreases or does not modify the effects of the individual neurotoxicants. Perinatal exposure to PCB126, PCB153 or MeHg impaired the function of the glutamate–NO–cGMP pathway in cerebellum and learning ability. However, co-exposure to PCB126+MeHg or PCB153+MeHg inhibits the impairment of the pathway or learning ability. These results support that the function of this pathway modulates learning of the Y maze task. Moreover, they show that co-exposure to these PCBs and MeHg does not exacerbate, but reduces the effects on the ability to learn this task. [Copyright &y& Elsevier]

Abstract: Manganese-enhanced magnetic resonance imaging (MEMRI) is receiving increased interest as a valuable tool for monitoring the physiological functions in the animal brain based on the ability of manganese ions to mimic calcium ions entering to excitable cells. Here the possibility that in vivo MEMRI can detect the entry of manganese ions (Mn2+) in the brain of rats behaving without intended stimulation is tested. This hypothesis was a result of the unexpected observation that Mn2+-dependent signal enhancement was dramatically suppressed in ketamine-anesthetized rats compared with other anesthetics, such as urethane, pentobarbital and isoflurane. The effects of noncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonists, ketamine and MK-801, on MEMRI for MnCl2 injected rats were examined. Treatment with MK-801 suppressed the signal enhancement more effectively than with ketamine. NMDAR agonists, glutamate (100 mg/kg) and N-methyl-d-aspartate (NMDA) (35 mg/kg), enhanced the signal intensities on MEMRI, and this signal enhancement was completely antagonized by MK-801. The systemic administration of the competitive NMDAR antagonist, d-2-amino-5-phosphono-pentanoate (d-AP5), which does not cross the blood–brain barrier (BBB), showed no effects on the signal enhancement induced by NMDA and glutamate. A selective AMPA receptor (AMPAR) antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), did not block the signal enhancement. These data indicated that the Mn2+-dependent signal enhancement took place as a result of the activation of glutamatergic neurons through NMDAR, but not through AMPAR in the brain. [Copyright &y& Elsevier]

Abstract: The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia. [Copyright &y& Elsevier]

Abstract: The effects of repeated administration of a tricyclic antidepressant, imipramine, lasting 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. In slices prepared from imipramine-treated animals the mean frequency, and to a lesser degree the mean amplitude, of spontaneous excitatory postsynaptic currents recorded from layer II/III pyramidal neurons, were decreased. These effects were accompanied by a reduction of the initial slope ratio of pharmacologically isolated N-methyl-d-aspartate to AMPA/kainate receptor-mediated stimulation-evoked excitatory postsynaptic currents. Imipramine treatment also resulted in a decrease of extracellular field potentials evoked in layer II/III by stimulation of underlying sites in layer V. These results indicate that chronic treatment with imipramine results in an attenuation of the release of glutamate and an alteration in the postsynaptic reactivity of ionotropic glutamate receptors in rat cerebral cortex. [Copyright &y& Elsevier]

Abstract: NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801. Consistent with a selective coupling of extrasynaptic NMDA receptors to the dominant ERK shutoff pathway, pre-block of synaptic NMDA receptors with MK-801 did not alter the inhibitory effect of bath-applied NMDA on ERK activity. Lastly, in contrast to a complete block of synaptic NMDA receptor activation of ERK by extrasynaptic NMDA receptors, activation of extrasynaptic NMDA receptors had no effect upon ERK activation by brain-derived neurotrophic factor. These results suggest that the synaptic NMDA receptor ERK activation pathway is coupled to both NR2A and NR2B containing receptors, and that the extrasynaptic NMDA receptor ERK inhibitory pathway is not a non-selective global ERK shutoff. [Copyright &y& Elsevier]

Abstract: Thyroid hormones (THs) are well known for their genomic effects but recently attention has focused also on their nongenomic actions as rapid modulators of membrane receptors. Here we show that thyroxine (T4) and 3,3′,5′-l-triiodothyronine (T3) rapidly decrease N-methyl-d-aspartate (NMDA)-evoked currents in rat hippocampal cultures with potency in the micromolar range. The effect is not mediated by glutamate or glycine binding sites as an increase in agonist or glycine concentration does not alter TH potencies. Furthermore THs’ effect on NMDA receptors is independent of voltage and of subunit composition. The mechanism of THs’ antagonistic effect does not involve PKC phosphorylation of NMDA receptors since neither blocking nor stimulating PKC changed THs’ modulation. T3, but not T4, inhibits also kainate-evoked currents in hippocampal neurons in culture. In hippocampal pyramidal neurons in slice, T3, but not T4, significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude and decay. In cultured rat cortical neurons THs prevented glutamate-induced neuronal death at concentrations similar to those effective on glutamatergic receptors. Taken together our data show for the first time that THs can rapidly affect ionotropic glutamatergic receptors in hippocampal neurons, an effect that could have an important role in their modulation of brain function in physiological and pathological states. [Copyright &y& Elsevier]

Abstract: Methylmalonic acid (MMA) is an endogenous convulsing compound that accumulates in methylmalonic acidemia, an inborn error of the metabolism characterized by severe neurological dysfunction, including seizures. The mechanisms by which MMA causes seizures involves the activation of the N-methyl-d-aspartate (NMDA) receptors, but whether GABAergic mechanisms are involved in the convulsions induced by MMA is not known. Therefore, in the current study we investigated the involvement of GABAergic mechanisms in the convulsions induced by MMA. Adult rats were injected (i.c.v.) with muscimol (46 pmol/1 μl), baclofen (0.03, 0.1 and 0.3 μmol/1 μl), MK-801 (6 nmol/1 μl), pyridoxine (2 μmol/4 μl) or physiological saline (0.15 μmol/1 μl). After 30 min, MMA (0.3, 0.1 and 3 μmol/1 μl) or NaCl (6 μmol/1 μl, i.c.v.) was injected. The animals were immediately transferred to an open field and observed for the appearance of convulsions. After behavioral evaluation, glutamic acid decarboxylase (GAD) activity was determined in cerebral cortex homogenates by measuring the 14CO2 released from l-[14C]-glutamic acid. Convulsions were confirmed by electroencephalographic recording in a subset of animals. MMA caused the appearance of clonic convulsions in a dose-dependent manner and decreased GAD activity in the cerebral cortex ex vivo. GAD activity negatively correlated with duration of MMA-induced convulsions (r=−0.873, P<0.01), in an individual basis. Muscimol, baclofen, MK-801 and pyridoxine prevented MMA-induced convulsions, but only MK-801 and pyridoxine prevented MMA-induced GAD inhibition. These data suggest GABAergic mechanisms are involved in the convulsive action of MMA, and that GAD inhibition by MMA depends on the activation of NMDA receptors. While in this study we present novel data about the role of the GABAergic system in MMA-induced convulsions, the central role of NMDA receptors in the neurochemical actions of MMA is further reinforced since they seem to trigger GABAergic failure. [Copyright &y& Elsevier]

Abstract: Subiculum receives output of hippocampal CA1 neurons and projects glutamatergic synapses onto nucleus accumbens (NAc), the subicular–NAc pathway linking memory and reward system. It is unknown whether morphine withdrawal influences synaptic plasticity in the subicular–NAc pathway. Here, we recorded the field excitatory postsynaptic potential (EPSP) within the shell of NAc by stimulating ventral subiculum in anesthetized adult rats. We found that high frequency stimulation (HFS, 200 Hz) induced long-term potentiation (LTP) but low frequency stimulation (LFS, 1 Hz) failed to induce long-term depression (LTD) in control animals. However, behavioral stress enabled LFS to induce a reliable LTD (sLTD) that was dependent on the glucocorticoid receptors. Both LTP and sLTD were prevented by the N-methyl-d-aspartate receptor antagonist AP-5. After repeated morphine treatment for 12 days, acute withdrawal (12 h) impaired LTP but had no effect on sLTD; prolonged withdrawal (4 days) restored the LTP but impaired the sLTD. Remarkably, basal synaptic efficacy reflected by baseline EPSP amplitude was potentiated in acute withdrawal but was depressed in prolonged withdrawal. Thus, acute and prolonged opiate withdrawal may cause endogenous LTP and LTD in the subicular–NAc pathway that occludes the subsequent induction of synaptic plasticity, demonstrating adaptive changes of the NAc functions during opiate withdrawal. [Copyright &y& Elsevier]

Abstract: Neuronal nitric oxide synthase, the major nitric oxide synthase isoform in the mammalian brain, is implicated in some developmental processes, including neuronal survival, precursor proliferation and differentiation. However, reports about the role of neuronal nitric oxide synthase in neurogenesis in the adult dentate gyrus are conflicting. Here we show that 5-bromodeoxyuridine-labeled dividing progenitor cells in the dentate gyrus were significantly increased in mice receiving 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, and in null mutant mice lacking neuronal nitric oxide synthase gene (nNOS−/−) 6 h and 4 weeks after 5-bromodeoxyuridine incorporation. The increase in 5-bromodeoxyuridine positive cells in 7-nitroindazole-treated mice was accompanied by activation of cyclic AMP response element binding protein phosphorylation in the dentate gyrus. Pretreatment with N-methyl-d-aspartate receptor antagonist MK-801 fully abolished the effects of 7-nitroindazole on neurogenesis and cyclic AMP response element binding protein phosphorylation. Furthermore, neuronal nitric oxide synthase inhibition significantly enhanced the survival of newborn cells and the number of 5-bromodeoxyuridine positive/NeuN positive cells in the dentate gyrus. These results indicate that neuronal nitric oxide synthase-derived nitric oxide suppresses neurogenesis in the adult dentate gyrus, in which N-methyl-d-aspartate receptor functions and cyclic AMP response element binding protein phosphorylation may be involved. [Copyright &y& Elsevier]

Abstract: Gymnotid electric fish explore their environment and communicate with conspecifics by means of rhythmic electric organ discharges. The neural command for each electric organ discharge arises from activity of a medullary pacemaker nucleus composed of two neuronal types: pacemaker and relay cells. During different behaviors as in courtship, exploration and agonistic interactions, these species display specific electric organ discharge frequency and/or waveform modulations. The neural bases of these modulations have been explained in terms of segregation of inputs to pacemaker or relay cells, as well as differential activation of the glutamate receptors of these cells. One of the most conspicuous electric organ discharge frequency modulations in Gymnotus carapo results from the activation of Mauthner cells, a pair of reticulospinal neurons that are involved in the organization of sensory-evoked escape responses in teleost fish. The activation of Mauthner cells in these animals produces a prolonged increase in electric organ discharge rate, whose neural mechanisms involves the activation of both N-methyl-d-aspartate (NMDA) and metabotropic glutamatergic receptors of pacemaker cells. Here we provide evidence which indicates that pacemaker cells are the only cellular target of the synaptic inputs responsible for the Mauthner cell initiated electric organ discharge modulation at the medullary pacemaker nucleus. Additionally, although pacemaker cells express both NMDA and non-NMDA ionotropic receptors, we found that non-NMDA receptors are not involved in this synaptic action which suggests that NMDA and non-NMDA receptor subtypes are not co-localized at the subsynaptic membrane. NMDA receptor activation of pacemaker cells seems to be an efficient neural strategy to produce long-lasting enhancements of the fish sampling capability during Mauthner cell-initiated motor behaviors. [Copyright &y& Elsevier]

Abstract: Progestins mediate the onset and duration of lordosis, the mating posture of female rodents, through actions in the hypothalamus and ventral tegmental area. In the hypothalamus, progesterone has traditional, “genomic” actions via intracellular progestin receptors. In the ventral tegmental area, 3α-hydroxy-5α-pregnan-20-one has “non-genomic” actions independent of progestin receptors to facilitate lordosis that involve GABAA/benzodiazepine receptors, NMDA type glutamate receptors, and/or dopamine receptors. 3α-Hydroxy-5α-pregnan-20-one levels also change with behavioral and/or environmental stimuli and may have a role in other reproductively-relevant behaviors, such as affiliation, exploration, and anxiety (socio-sexual behaviors). Data are reviewed that support the notion that: 1) effects of 3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area facilitate lordosis and other reproductively-relevant behaviors. 2) 3α-Hydroxy-5α-pregnan-20-one, formed in the ventral tegmental area from metabolism of progestins, produced peripherally by endocrine glands, or centrally from biosynthesis in glial cells mediates socio-sexual behaviors. 3) 3α-Hydroxy-5α-pregnan-20-one’s actions at GABAA/benzodiazepine receptors, NMDA type glutamate receptors, and dopamine receptors in the ventral tegmental area are important for lordosis; however, effects at these substrates on socio-sexual behaviors have not been elucidated. Given 3α-hydroxy-5α-pregnan-20-one’s involvement in stress responses, its putative role as a homeostatic regulator and in the pathophysiology and treatment of neuropsychiatric disorders is discussed. [Copyright &y& Elsevier]

Abstract: Zinc ions (Zn2+) are known to modulate the functions of a variety of channels, receptors and transporters. We examined the effects of Zn2+ on the reflex potentials evoked by electrical stimulation and responses to depolarizing agents in the isolated spinal cord of the neonatal rat in vitro. Zn2+ at low concentrations (0.5–2μM) inhibited, but at high concentrations (5 and 10μM) augmented, a slow depolarizing component (slow ventral root potential). Zn2+ had no effect on fast components (monosynaptic reflex potential; fast polysynaptic reflex potential). Unlike Zn2+, strychnine (5μM), a glycine receptor antagonist, and (S),9(R)-(−)-bicuculline methobromide (10μM), a GABAA receptor antagonist, potentiated both fast polysynaptic reflex potential and slow ventral root potential. Zn2+ (5μM) did not affect depolarizing responses to glutamate and N-methyl-d-aspartate. Zn2+ enhanced the substance P-evoked depolarization in the absence of tetrodotoxin (0.3μM) but not in its presence. The dorsal root potential was inhibited by (S),9(R)-(−)-bicuculline methobromide (10μM) but not by Zn2+ (5μM). The Zn2+-potentiated slow ventral root potential was inhibited by the N-methyl-d-aspartate receptor antagonists, ketamine (10μM) and dl-2-amino-5-phosphaonovaleric acid (50μM) but not by P2X receptor antagonists, pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid (30μM) and 2′,3′-O-(2,4,6-trinitrophenyl)ATP (10μM). Ketamine (10μM) and dl-2-amino-5-phosphaonovaleric acid (50μM) almost abolished spontaneous activities increased by Zn2+. It is concluded that Zn2+ potentiated slow ventral root potential induced by primary afferent stimulation, which was mediated by the activation of N-methyl-d-aspartate receptors but not by activation of P2X receptors or blockade of glycinergic and GABAergic inhibition. Zn2+ does not seem to directly affect N-methyl-d-aspartate receptors. The release of glutamate from interneurons may play an important role in Zn2+-induced potentiation of slow ventral root potential in the spinal cord of the neonatal rat. [Copyright &y& Elsevier]

Abstract: Glutamate is the main neurotransmitter at the synapses between sensory cells and primary afferents in the peripheral vestibular system. Evidence has recently been obtained demonstrating that the atypical amino acid d-serine is the main endogenous co-agonist of the N-methyl-d-aspartate receptors in the CNS. We studied the distribution of d-serine and its synthesizing and degrading enzymes, serine racemase and d-amino acid oxidase in the rat vestibular sensory epithelium using immunocytochemistry. d-Serine, serine racemase and d-amino acid oxidase were localized in the transitional cells, which are parasensory cells located between the sensory epithelium and the dark cells. The dark cells expressed only serine racemase. d-Serine was also detected in the supporting cells of the sensory epithelium. These cells, which are in close contact with glutamatergic synapses, express GLAST, a glial specific transporter for glutamate. They may have similar functions to glial cells in the CNS and thus expression of d-serine suggests a neuromodulator role for d-serine at the glutamatergic synapses in the peripheral vestibular system. Our data also indicate that the metabolism of d-serine is not restricted to glial cells suggesting that the amino acid may play an additional role in the peripheral nervous system. [Copyright &y& Elsevier]

The sulphur-containing amino acid homocysteic acid (HCA) is present in and released in vitro from nervous tissue and is a potent neuronal excitant, predominantly activating N-methyl-d-aspartate (NMDA) receptors. However, HCA is localised not in neurones but in glial cells [Eur J Neurosci 3 (1991) 1370], and we have shown that it is released from astrocytes in culture upon glutamate receptor activation [Neuroscience 124 (2004) 377]. We now report the in vivo release of HCA from ventrobasal (VB) thalamus following natural stimulation of somatosensory afferents arising from the facial vibrissae of the rat. Simultaneously with multi-unit recording, [35S]-methionine, a HCA precursor, was perfused through a push-pull cannula in VB thalamus of anaesthetized rats. Perfusates were collected before, during and after 4 min stimulation of the vibrissal afferents with an air jet. A marked release of radiolabeled HCA was observed during and after the stimulation. Furthermore, the β-adrenoreceptor agonist isoproterenol, which is known to evoke HCA release from glia in vitro, was found to increase the efflux of HCA in the perfusate in vivo. In separate experiments, the excitatory actions of iontophoretically applied HCA on VB neurones were inhibited by the NMDA receptor antagonist CPP, but not by the non-NMDA antagonist CNQX. These results suggest a possible “gliotransmitter” role for HCA in VB thalamus. The release of HCA from glia might exert a direct response or modulate responses to other neurotransmitters in postsynaptic neurons, thus enhancing excitatory processes. [Copyright &y& Elsevier]

The activation of spinal cord N-methyl-d-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 μg/10 μl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 μg/10 μl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 μg/10 μl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function.The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance. [Copyright &y& Elsevier]

Dynorphin A (1–17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1–17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-d-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (−)-naloxone, a general opioid antagonist. The results show that dynorphin A (1–17) (≥10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors. [Copyright &y& Elsevier]

The effects of repeated administration of a tricyclic antidepressant, imipramine, and a selective serotonin reuptake blocker, citalopram, for 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. Treatment with both antidepressants resulted in a decrease in the amplitude of field potentials evoked in layer II/III by stimulation of underlying sites in layer V. The amplitude ratio of pharmacologically isolated N-methyl-d-aspartic acid (NMDA) to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor-mediated components of the field potential was reduced. These results indicate that chronic treatment with imipramine or citalopram results in an attenuation of glutamatergic synaptic transmission in the cerebral cortex. [Copyright &y& Elsevier]

We used field potential and intracellular recordings in rat brain slices that included the hippocampus, a portion of the basolateral/lateral nuclei of the amygdala (BLA) and the entorhinal cortex (EC). Bath application of the convulsant 4-aminopyridine (50 μM) to slices (n=12) with reciprocally connected areas, induced short-lasting interictal-like epileptiform discharges that (i) occurred at intervals of 1.2–2.8 s, (ii) originated in CA3, and (iii) spread to EC and BLA. Cutting the Schaffer collaterals abolished them in both parahippocampal areas where slower interictal-like (interval of occurrence=4–17 s) and prolonged ictal-like discharges (duration=15±6.9 s, mean±S.D., n=7) appeared. These new types of epileptiform activity originated in either EC or BLA. Similar findings were obtained in slices (n=19) in which the hippocampus outputs were not connected with the EC and BLA under control conditions. Cutting the EC–BLA connections made independent slow interictal- and ictal-like activities appear in both areas (n=5). NMDA receptor antagonism (n=6) abolished ictal-like discharges and reduced the duration of the slow interictal-like events. Repetitive stimulation of BLA at 0.5–1 Hz in Schaffer collateral cut slices, induced interictal-like epileptiform depolarizations in EC and reversibly blocked ictal-like activity (n=14). Thus, CA3 outputs in intact slices entrain EC and BLA networks into an interictal-like pattern that inhibits the propensity of these parahippocampal areas to generate prolonged ictal-like paroxysms. Accordingly, NMDA receptor-dependent ictal-like events are initiated in BLA or EC once the propagation of CA3-driven interictal-like discharges to these areas is abated by cutting the Schaffer collaterals. Similar inhibitory effects also occur by activating BLA outputs directed to EC at rates that mimic the CA3-driven interictal-like pattern. [Copyright &y& Elsevier]

The α5β1 integrin is present in high concentrations in the apical dendrites of pyramidal neurons in adult rats but is virtually absent in the basal dendrites. Moreover, α5β1 does not appear in apical dendritic branches until the third post-natal week. Given that integrins contribute to the consolidation of synaptic plasticity, these results raise the possibility of developmental and regional differences in the stability of long-term potentiation (LTP). The present study tested this point using a LTP reversal paradigm in field CA1 of hippocampal slices. In accord with earlier reports, low-frequency afferent stimulation (5 Hz) introduced 30 s after theta burst stimulation (TBS) completely reversed LTP but was ineffective 30 min and 60 min later in slices from adult rats. The same low-frequency trains caused a partial reversal of LTP when applied 30 and 60 min post-TBS in slices from 21-day-old rats and a complete reversal at all time points in slices from 10-day-old rats. LTP in the basal dendrites of adult rats did not fully consolidate; i.e. potentiation was partially reversed by low-frequency stimulation even after delays of 30 or 60 min. Moreover, spaced (10 min) applications of 5- Hz pulses beginning at 30 min post-TBS completely erased LTP. The reversal effect in both apical and basal dendrites was blocked by N-methyl-D-aspartic acid receptor antagonists but an integrin antagonist had differential effects across the two dendritic domains. These results constitute evidence that the stability of LTP increases with age in the apical dendrites but remains incomplete even in adulthood in the basal dendrites. The possibilities that the developmental and regional variations in LTP consolidation are correlated with integrin expression and linked to different types of memory processing are discussed. [Copyright &y& Elsevier]

Neonatal rats survive and avoid brain injury during periods of anoxia 25 times longer than adults. We hypothesized that oxygen activates and hypoxia suppresses NMDA receptor (NMDAR) responses in neonatal rat neurons, explaining the innate hypoxia tolerance of these cells. In CA1 neurons isolated from neonatal rat hippocampus (mean postnatal age [P] 5.8 days), hypoxia (PO2 10 mm Hg) reduced NMDA receptor-channel open-time percentage and NMDA-induced increase in [Ca2+]i (NMDA ΔCa2+) by 38 and 68% (P<0.01), respectively. In P20 neurons the reductions were not significant. In P3–10 CA1 neurons within intact hippocampal slices, hypoxia reduced NMDA ΔCa2+ by 52% (P=0.002) and decreased NMDA-induced death by 45% (P=0.004). Phalloidin, a microtubule stabilizer, prevented hypoxia-induced inhibition of NMDA ΔCa2+ in P3–10 neurons. To test whether NMDARs prevalent in neonates (NR1 plus NR2B or NR2D subunits) are inhibited by hypoxia compared with those in mature neurons (NR2A and NR2C), we expressed these receptors in Xenopus oocytes. Compared with responses in 21% O2, hypoxia (PO2 17 mm Hg) reduced currents from neonatal type NR1/NR2D receptors by 25%, increased currents from NR1/NR2C by 18%, and had no effect on NR1/NR2A or NR1/NR2B. Modulation of NMDARs by hypoxia may play an important role in the hypoxia tolerance of the mammalian neonate. In addition, oxygen sensing by NMDARs could play a significant role in postnatal brain development. [Copyright &y& Elsevier]

The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau₄₅₋₂₃₀ fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau₄₅₋₂₃₀ and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau₄₅₋₂₃₀ mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau₄₅₋₂₃₀ is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)