Dysfunction Of Glutamatergic Neurotransmission Research Articles

The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Alterations of the glutamatergic system in diabetes mellitus.

Diabetes mellitus (DM) is a chronic disease characterized by elevated blood glucose levels caused by a lack of insulin production (type 1 diabetes) or insulin resistance (type 2 diabetes). It is well known that DM is associated with cognitive deficits and metabolic and neurophysiological changes in the brain. Glutamate is the main excitatory neurotransmitter in the central nervous system that plays a key role in synaptic plasticity, learning, and memory processes. An increasing number of studies have suggested that abnormal activity of the glutamatergic system is implicated in the pathophysiology of DM. Dysfunction of glutamatergic neurotransmission in the central nervous system can provide an important neurobiological substrate for many disorders. Magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows a better understanding of the central nervous system factors by measuring in vivo the concentrations of brain metabolites within the area of interest. Here, we briefly review the MRS studies that have examined glutamate levels in the brain of patients with DM. The present article also summarizes the available data on abnormalities in glutamatergic neurotransmission observed in different animal models of DM. In addition, the role of gut microbiota in the development of glutamatergic alterations in DM is addressed. We speculate that therapeutic strategies targeting the glutamatergic system may be beneficial in the treatment of central nervous system-related changes in diabetic patients.

Phosphorylated Ser187-SNAP25-modulated hyperfunction of glutamatergic system in the vmPFC mediates depressive-like behaviors in male mice

Dysfunctional glutamatergic neurotransmission contributes importantly to the pathophysiology of depression. However, the underlying neural mechanisms of glutamatergic dysfunction remain poorly understood. Here, we employed chronic unpredictable mild stress (CUMS) to induce depression-like behavior in male mice and to assess the alterations of glutamatergic system within the ventromedial prefrontal cortex (vmPFC). Male mice subjected to CUMS showed an increase in levels of glutamate content, synaptosomal GluN2B-NMDA receptors (GluN2B-NMDARs) and phosphorylated synaptosomal associated protein 25 KD of Ser187 (pSer187-SNAP25), which is involved in synaptic vesicular fusion processes in the vmPFC. Downregulation of pSer187-SNAP25 via the TAT-S187 fusion peptide efficiently alleviated CUMS-induced depressive-like behaviors in male mice by reversing the increase of glutamate content and synaptosomal GluN2B-NMDARs. These findings demonstrated a critical role for pSer187-SNAP25-mediated glutamatergic dysfunction in CUMS-induced depressive-like behaviors, suggesting the potential of pS187-SNAP25 inhibitors for further investigation on depression management.

Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice.

Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 administration at effective (50mg/kg) or subeffective (1mg/kg) dosesby intragastric route (ig). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1pmol/site, intracerebroventricular, icv, a selective agonist of the NMDA receptors), D-serine (30µg/site, icv, a co-agonist at the NMDA receptor), arcaine (1mg/kg, intraperitoneal, ip, an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5µg/site, icv, an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF1 (50mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 with low doses of MK-801 (0.001mg/kg, ip, a non-competitive NMDA receptor antagonist) or ketamine (0.1mg/kg, ip, a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.

Absence of VGLUT3 Expression Leads to Impaired Fear Memory in Mice.

Fear is an emotional mechanism that helps to cope with potential hazards. However, when fear is generalized, it becomes maladaptive and represents a core symptom of posttraumatic stress disorder (PTSD). Converging lines of research show that dysfunction of glutamatergic neurotransmission is a cardinal feature of trauma and stress related disorders such as PTSD. However, the involvement of glutamatergic co-transmission in fear is less well understood. Glutamate is accumulated into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The atypical subtype, VGLUT3, is responsible for the co-transmission of glutamate with acetylcholine, serotonin, or GABA. To understand the involvement of VGLUT3-dependent co-transmission in aversive memories, we used a Pavlovian fear conditioning paradigm in VGLUT3-/- mice. Our results revealed a higher contextual fear memory in these mice, despite a facilitation of extinction. In addition, the absence of VGLUT3 leads to fear generalization, probably because of a pattern separation deficit. Our study suggests that the VGLUT3 network plays a crucial role in regulating emotional memories. Hence, VGLUT3 is a key player in the processing of aversive memories and therefore a potential therapeutic target in stress-related disorders.

Importance of Exploring N-Methyl-D-Aspartate (NMDA) as a Future Perspective Target in Depression.

Major depressive disorder (MDD) is a serious and complex mental illness. Currently, many antidepressants are available in the market for the treatment of MDD. However, these agents are associated with side effects, which restricts their use. This warrants the development of advanced antidepressive medications with a novel mechanism of action or novel targets and with minimal adverse effects. The traditional neurobiological hypothesis of depression, the monoamine hypothesis, is unable to properly explain all the aspects of depressive conditions. In this review, we discuss novel approaches that could be used for the treatment of depression, including glutamatergic and serotonergic system modulation. The pathogenesis of depression is greatly affected by glutamatergic neurotransmission dysfunction. Previous investigations have shown that ketamine, an N-methyl-D-aspartate receptor antagonist, exerts fast and long-lasting antidepressant effects. Several glutamatergic modulators, such as esketamine, sarcosine, and others, have also shown potential antidepressant action in animal as well as clinical studies. Lastly, drugs that alter neurotransmission by NMDA receptors could open up new avenues for more effective treatment of depression. Besides, understanding the underlying mechanisms will aid in the development of novel and fast-acting antidepressant drugs in the future.

Early postnatal inhibition of GLAST causes abnormalities of psychobehaviors and neuronal morphology in adult mice

The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl-threo-β-benzyloxyaspartate (dl-TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl-TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.

Social preference is maintained in mice with impaired startle reflex and glutamate/D-serine imbalance induced by chronic cerebral toxoplasmosis

Toxoplasma gondii is an opportunistic protozoan pathogen with a wide geographic distribution. The chronic phase of toxoplasmosis is often asymptomatic in humans and is characterized by tissue cysts throughout the central nervous system and muscle cells. T. gondii and other pathogens with tropism for the central nervous system are considered risk factors in the etiology of several neuropsychiatric disorders, such as schizophrenia and bipolar disorder, besides neurological diseases. Currently, it is known that cerebral toxoplasmosis increases dopamine levels in the brain and it is related to behavioral changes in animals and humans. Here we evaluate whether chronic T. gondii infection, using the cystogenic ME-49 strain, could induce behavioral alterations associated with neuropsychiatric disorders and glutamatergic neurotransmission dysfunction. We observed that the startle amplitude is reduced in the infected animals as well as glutamate and D-serine levels in prefrontal cortical and hippocampal tissue homogenates. Moreover, we did not detect alterations in social preference and spontaneous alternation despite severe motor impairment. Thus, we conclude that behavioral and cognitive aspects are maintained even though severe neural damage is observed by chronic infection of C57Bl/6 mice with the ME-49 strain.

Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes.

Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells-neurons and oligodendrocytes-treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients' postmortem brains.

Vitamin D and N-Acetyl Cysteine Supplementation in Treatment-Resistant Depressive Disorder Patients: A General Review.

Major Depressive Disorder (MDD) is often a lifetime disabling mental illness as individuals with MDD might not benefit from standard-therapy, including both pharmacological and psychosocial interventions. Novel therapies are, therefore, required. It was shown by recent preclinical and clinical studies that the dysfunction of glutamatergic neurotransmission might be involved in the pathophysiology of MDD. Furthermore, neuroimmune alterations could have a significant role in the pathogenesis of MDD. Vitamin D is a neurosteroid hormone essential for several metabolic processes, immune responses, and for regulating neurotrophic-neuroprotective processes, neurotransmission and synaptic plasticity. Recent studies have also shown Vitamin D deficiency in patients with severe psychiatric disorders, including MDD. Lately, clinical studies have shown the neuroprotective action of N-acetyl cysteine (NAC) through the modulation of inflammatory pathways and via the modulation of synaptic release of glutamate in cortico-subcortical brain regions; the cysteine-glutamate antiporter. This paper reviews the therapeutic use of Vitamin D and NAC and among individuals with refractory MDD to the first- line pharmacological interventions, reviewing the clinical studies published in the last decade. A detailed summary of the current evidence in this area aims to better inform psychiatrists and general practitioners on the potential benefits of Vitamin D and NAC supplementation for this disorder. Nutraceutical supplementation with Vitamin D and NAC in treatment-resistant MDD patients may be important not only for improving depressive clinical manifestations but also for their safety and tolerability profile. This is of great interest, especially considering the need for treating special populations affected by MDD, such as youngsters and elders. Finally, the nutraceutical approach represents a good choice, considering its better compliance by the patients compared to traditional psychopharmacological treatment.

Attenuation of oxidative stress and neurotoxicity involved in the antidepressant-like effect of the MK-801(dizocilpine) in Bacillus Calmette-Guerin-induced depression in mice.

Background The emerging line of research suggests that neuro-inflammation and oxidative stress are linked to the development of depression-like behavior. The tryptophan metabolizing enzyme, indolamine 2,3-dioxygenase (IDO), serves as an important interface between chronic inflammation and depression. IDO is induced by pro-inflammatory cytokines and diverts tryptophan towards the kynurenine pathway, decreasing serotonin synthesis. Further, the metabolites of kynurenine pathway increase brain oxidative stress and also cause N-methyl-D-aspartate (NMDA) receptor-mediated exitotoxicity. The resulting oxidative damage and dysfunction in glutamatergic neurotransmission alters the network connectivity of the brain, which may be the further mechanism for emergence of depression-like symptoms. Methods A depression-like illness was induced in mice by injecting Bacillus Calmette-Guerin (BCG) suspended in isotonic saline at a dose of 107 CFU I.P. The mice were then divided into different groups and were administered MK-801 or normal saline for the next 21 days, after which a battery of behavior and biochemical tests were conducted to assess them. Results The BCG group had significantly reduced sucrose preference index and an increase in immobility time in forced swim test (FST) and Tail Suspension Test (TST) as compared to the saline group. There was also a significant increase in the brain MDA levels and a decline in the brain GSH levels. The hippocampal tissue from the BCG group had significantly more comet cells than the saline group. The NMDA receptor antagonist, MK-801, was able to reverse the BCG-induced depression-like behaviour. MK-801 also showed significant decrease in brain oxidative stress but failed to show significant protection against BCG-induced neurotoxicity observed in comet assay. Conclusions The NMDA receptor antagonist, MK-801, mitigated BCG-induced, depressive-like behavior in mice by improving the sucrose preference and decreasing the duration of immobility time in TST and FST. The overall improvement in depression-like behavior was accompanied by a reduction in brain oxidative stress and comet cells, thus suggesting the antioxidant and neuroprotective action of MK-801.

Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments.

The underlying neurobiological basis of major depressive disorder remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of major depressive disorder, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment-resistant depression have prompted tremendous interest in understanding the mechanisms responsible for ketamine’s clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine’s effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine’s targets include noncompetitive N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation coupled with downstream signaling changes, and N-methyl-D-aspartate receptor targets localized on gamma-aminobutyric acid-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for treatment-resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described.

Вплив стресу на поведінку і сон. Кортизол: гормон стресу чи гормон пробудження?

This review is dedicated to the role of cortisol in behavior and sleep grounded on evidence-based information that acute and chronic stress (in particular the stress-induced release of glucocorticoids), induce changes in glutamate neurotransmission in prefrontal cortex and hippocampus, and infl uence cognitive processing. Dysfunction of glutamatergic neurotransmission is indeed more considered pivotal in stress-related neuropsychiatric disorders. Sleep is important for memory consolidation. Recently new data has shown the multifaceted nature of sleep-related motor memory consolidation. Intriguingly, motor learning does not alone take place during the actual task but also between training sessions including periods of sleep. Knowing that sleep may increase performance of motor tasks in subsequent retests, an effect specifi c to the sleep towards the end of the sleep cycle, when receptor occupancies will change. That cortisol profi les show individual diurnal rhythms warrants further appreciation of the pivotal role of cortisol in sleepwake physiology and behavioural performance. It is safe to conclude that cortisol is a hormone during wake and during sleep.

Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex

Objectives: Attention-deficit/hyperactivity disorder (ADHD) is closely linked to the dysregulation of dopaminergic and noradrenergic neurotransmission in the fronto-striatal neural network, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). Additionally, increasing evidence supports the involvement of the glutamatergic system in the pathophysiology of ADHD. Impulsivity, a core symptom in patients with ADHD, has been repeatedly associated with glutamatergic neurotransmission, and pharmacological treatment of ADHD has been shown to reduce glutamate levels in the prefrontal cortex.Methods: We investigated glutamate levels in the ACC and the DLPFC in 30 adults with ADHD and 30 healthy controls using single-voxel proton magnetic resonance spectroscopy on a 3T scanner.Results: The ADHD group showed a significant increase in glutamate in the ACC compared to controls, no significant differences in metabolites were observed in the DLPFC. Overall, glutamate levels in the ACC were positively correlated with ADHD symptomatology, especially hyperactivity and impulsivity symptoms.Conclusions: Increased levels of glutamate in the ACC, which were positively correlated with hyperactivity and impulsivity, support the hypothesis that dysfunctional glutamatergic neurotransmission is at least partially responsible for ADHD symptomatology. Modulation of glutamatergic neurotransmission might therefore be a promising avenue for future pharmacological interventions.

Tumor necrosis factor-mediated downregulation of spinal astrocytic connexin43 leads to increased glutamatergic neurotransmission and neuropathic pain in mice.

Spinal cord astrocytes are critical in the maintenance of neuropathic pain. Connexin 43 (Cx43) expressed on spinal dorsal horn astrocytes modulates synaptic neurotransmission, but its role in nociceptive transduction has yet to be fully elaborated. In mice, Cx43 is mainly expressed in astrocytes, not neurons or microglia, in the spinal dorsal horn. Hind paw mechanical hypersensitivity was observed beginning 3days after partial sciatic nerve ligation (PSNL), but a persistent downregulation of astrocytic Cx43 in ipsilateral lumbar spinal dorsal horn was not observed until 7days post-PSNL, suggesting that Cx43 downregulation mediates the maintenance and not the initiation of nerve injury-induced hypersensitivity. Downregulation of Cx43 expression by intrathecal treatment with Cx43 siRNA also induced mechanical hypersensitivity. Conversely, restoring Cx43 by an adenovirus vector expressing Cx43 (Ad-Cx43) ameliorated PSNL-induced mechanical hypersensitivity. The sensitized state following PSNL is likely maintained by dysfunctional glutamatergic neurotransmission, as Cx43 siRNA-induced mechanical hypersensitivity was attenuated with intrathecal treatment of glutamate receptor antagonists MK801 and CNQX, but not neurokinin-1 receptor antagonist CP96345 or the Ca(2+) channel subunit α2δ1 blocker gabapentin. The source of this dysfunctional glutamatergic neurotransmission is likely decreased clearance of glutamate from the synapse rather than increased glutamate release into the synapse. Astrocytic expression of glutamate transporter GLT-1, but not GLAST, and activity of glutamate transport were markedly decreased in mice intrathecally injected with Cx43-targeting siRNA but not non-targeting siRNA. Glutamate release from spinal synaptosomes prepared from mice treated with either Cx43-targeting siRNA or non-targeting siRNA was unchanged. Intrathecal injection of Ad-Cx43 in PSNL mice restored astrocytic GLT-1 expression. The cytokine tumor necrosis factor (TNF) has been implicated in the induction of central sensitization, particularly through its actions on astrocytes, in the spinal cord following peripheral injury. Intrathecal injection of TNF in naïve mice induced the downregulation of both Cx43 and GLT-1 in spinal dorsal horn, as well as hind paw mechanical hypersensitivity, as observed in PSNL mice. Conversely, intrathecal treatment of PSNL mice with the TNF inhibitor etanercept prevented not only mechanical hypersensitivity but also the downregulation of Cx43 and GLT-1 expression in astrocytes. The current findings indicate that spinal astrocytic Cx43 are essential for the maintenance of neuropathic pain following peripheral nerve injury and suggest modulation of Cx43 as a novel target for developing analgesics for neuropathic pain.

Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder

The pathophysiology of bipolar disorder (BD) mostly remains unclear. However, some findings argue for a dysfunction in glutamatergic neurotransmission in BD. Proton magnetic resonance spectroscopy at 3T was used to determine glutamate concentrations in the anterior cingulate cortex (ACC) and the hippocampus (HC) of euthymic outpatients with BP-I disorder and age- and sex-matched healthy controls. In patients with BD, glutamate concentrations were significantly increased in the ACC and decreased in the HC compared with concentrations in controls. Significant group differences were also measured for N-acetyl aspartate and choline; no differences were found for other metabolites examined. An inverse correlation was observed for glutamate concentrations in the ACC and number of episodes. The findings of the study add to the concept of abnormalities in glutamatergic regulation in the ACC and HC in patients with BD.

Source-reconstruction of event-related fields reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode schizophrenia patients during Mooney face processing.

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.

Erratum: Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study

Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the 'narrowly' defined criteria for typical autism, whereas 13 met the 'broader phenotype'. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD--the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex--as well as in a parietal cortex 'control' region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the 'narrow' and 'broader' phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development.

NMDA Neurotransmission Dysfunction in Mild Cognitive Impairment and Alzheimer’s Disease

The prevalence of Alzheimer's disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.

Reversal of novelty-induced hyperlocomotion and hippocampal c-Fos expression in GluA1 knockout male mice by the mGluR2/3 agonist LY354740

Dysfunctional glutamatergic neurotransmission has been implicated in schizophrenia and mood disorders. As a putative model for these disorders, a mouse line lacking the GluA1 subunit (GluA1-KO) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor displays a robust novelty-induced hyperlocomotion associated with excessive neuronal activation in the hippocampus. Agonists of metabotropic glutamate 2/3 receptors (mGluR2/3) inhibit glutamate release in various brain regions and they have been shown to inhibit neuronal activation in the hippocampus. Here, we tested a hypothesis that novelty-induced hyperlocomotion in the GluA1-KO mice is mediated via excessive hippocampal neuronal activation by analyzing whether an mGluR2/3 agonist inhibits this phenotypic feature. GluA1-KO mice and littermate wildtype (WT) controls were administered with (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) (15mg/kg, i.p.) 30min before a 2-h exposure to novel arenas after which c-Fos immunopositive cells were analyzed in the hippocampus. LY354740 (15mg/kg) decreased hyperactivity in male GluA1-KO mice, with only a minimal effect in WT controls. This was observed in two cohorts of animals, one naïve to handling and injections, another pre-handled and accustomed to injections. LY354740 (15mg/kg) also reduced the excessive c-Fos expression in the dorsal hippocampal CA1 pyramidal cell layer in maleGluA1-KO mice, while not affecting c-Fos levels in WT mice. In female mice, no significant effect for LY354740 (15mg/kg) on hyperactive behavior or hippocampal c-Fos was observed in either genotype or treatment cohort. A higher dose of LY354740 (30mg/kg) alleviated hyperlocomotion of GluA1-KO males, but not that of GluA1-KO females. In conclusion, the excessive behavioral hyperactivity of GluA1-KO mice can be partly prevented by reducing neuronal excitability in the hippocampus with the mGluR2/3 agonist suggesting that the hippocampal reactivity is strongly involved in the behavioral phenotype of GluA1-KO mice.