The effects of memantine on prepulse inhibition.

Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

The role of GABA-B in sensorigating processing disorders in rat models, an autoradiographic study

INTRODUCTION: The process of sensorimotor gating is a neurological phenomenon referring to the brain’s ability to process and filter out stimuli in order to prevent an overflow of information. This phenomenon can be operationally measured by prepulse inhibition, which is the attenuation of a stimulus-induced startle response by introducing a milder preceding stimulus. Studies have shown that impairment of prepulse inhibition (PPI) has been correlated with diseases such as schizophrenia and autism spectrum disorder. Many brain areas, including the superior colliculus (SC), inferior colliculus (IC), mediodorsal thalamus (MD), basolateral amygdala (BLA), anterior cingulate cortex (ACC), and ventral hippocampus (VHPC), have been implicated in playing important roles in prepulse inhibition. While many studies have implicated GABA-A receptors in playing a role in PPI regulation, little work has been done on GABA-B receptors. An established rat model with induced prepulse inhibition impairment was used in this study. PPI impairment was induced via injection of the glutamate receptor antagonist dizocilpine. A subgroup of rats was also treated with the antihistamine pyrilamine to reverse the effects of dizocilpine. OBJECTIVES: The aims of this study are to: 1. Expand the understanding of prepulse inhibition in the context of neurological and developmental diseases such as autism spectrum disorder (ASD) and schizophrenia; 2. Identify potential significant differences within GABA-B receptor densities in the rat SC, IC, MD, BLA, ACC, or VHPC between treatment groups with and without dizocilpine and groups with and without pyrilamine. METHODS: Histological brain slides harvested from 36 Sprague-Dawley rats were provided by Dr. Edward Levin from Duke University’s Neurobehavioral Research Lab for this study. The brain slides were incubated in a radioligand solution specific for GABA-B receptors and exposed to autoradiograph film for approximately 12 weeks. The films were developed in a dark room and scanned electronically. GABA-B receptor densities were measured from the images and the data was analyzed using ANOVA and independent T tests. RESULTS: ANOVA testing revealed significant differences between treatment groups in the MD and VHPC. However, only the MD was found to have significant GABA-B receptor differences when comparing the dizocilpine and pyrilamine treatment groups to the control group. The VHPC was found to have significant differences in GABA-B receptor densities when directly comparing the dizocilpine group to the pyrilamine treatment group, rather than to the control group. There were no significant differences in GABA-B receptor densities as a result of either dizocilpine or pyrilamine treatment in the SC, IC, BLA, ACC, or VHPC. CONCLUSION: Changes in GABA-B receptor levels appear to play a role in both the impairment and rescue of PPI in the rat MD. It does not appear to play a role in the SC, IC, BLA, ACC, or VHPC for either the impairment or rescue of PPI function

Single subthalamic nucleus deep brain stimuli inhibit the blink reflex in Parkinson's disease patients

© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.The disordered output from the basal ganglia to the pontine tegmentum nuclei is considered responsible for a number of abnormalities in brainstem reflexes in patients with Parkinson's disease. One of the most conspicuous of these abnormalities is the reduced inhibition of the blink reflex by a prepulse stimulus. The circuit of prepulse inhibition involves structures and fibre groups that can be reached by stimuli applied through the electrodes implanted in the subthalamic nucleus for deep brain stimulation (STNDBS). In seven Parkinson's disease patients we examined whether single STNDBS induced prepulse effects on the blink reflex and how they compared with the effects induced by single auditory and somatosensory stimuli. Prepulse inhibition was determined by measuring the percentage inhibition induced in the R2 component of the orbicularis oculi response to supraorbital nerve stimuli. The inter-stimuli intervals (ISI) between the prepulse and the supraorbital nerve stimuli were 0 to 30 ms and 100 ms for single STNDBS and 100 ms for auditory and somatosensory modalities. The results obtained with acoustic and somatosensory stimuli were compared with those obtained from a group of 20 age-matched healthy subjects. Single STNDBS induced significant inhibition of the R2 in all patients at ISIs between 10 and 30 ms, with a mean percentage inhibition of 94% at the ISI of 30 ms. On the contrary, significant inhibition by auditory or somatosensory stimuli was induced in only two out of the seven patients. The mean percentage inhibition at the ISI of 100 ms was 37% for auditory and 40% for somatosensory stimuli, well below reference limits for prepulse inhibition in control subjects (61%). Single STNDBS induces significant prepulse inhibition of the blink reflex in Parkinson's disease patients who have abnormally reduced auditory and somatosensory prepulse effects. This finding helps define the prepulse circuit in humans and the eventual site of its dysfunction in Parkinson's disease.This work was in part accomplished thanks to grant P1040970 from FIS. J.C. has received a scholarship from the non-government Calouste Gulbenkian Foundationinfo:eu-repo/semantics/publishedVersio

Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca2+ channel peptides

Abstract: Modulation of presynaptic voltage-dependent Ca+ channels is a major means of controlling neurotransmitter release. The CaV 2.2 Ca2+ channel subunit contains several inhibitory interaction sites for Gβγ subunits, including the amino terminal (NT) and I–II loop. The NT and I–II loop have also been proposed to undergo a G protein-gated inhibitory interaction, whilst the NT itself has also been proposed to suppress CaV 2 channel activity. Here, we investigate the effects of an amino terminal (CaV 2.2[45–55]) ‘NT peptide’ and a I–II loop alpha interaction domain (CaV 2.2[377–393]) ‘AID peptide’ on synaptic transmission, Ca2+ channel activity and G protein modulation in superior cervical ganglion neurones (SCGNs). Presynaptic injection of NT or AID peptide into SCGN synapses inhibited synaptic transmission and also attenuated noradrenaline-induced G protein modulation. In isolated SCGNs, NT and AID peptides reduced whole-cell Ca2+ current amplitude, modified voltage dependence of Ca2+ channel activation and attenuated noradrenaline-induced G protein modulation. Co-application of NT and AID peptide negated inhibitory actions. Together, these data favour direct peptide interaction with presynaptic Ca2+ channels, with effects on current amplitude and gating representing likely mechanisms responsible for inhibition of synaptic transmission. Mutations to residues reported as determinants of Ca2+ channel function within the NT peptide negated inhibitory effects on synaptic transmission, Ca2+ current amplitude and gating and G protein modulation. A mutation within the proposed QXXER motif for G protein modulation did not abolish inhibitory effects of the AID peptide. This study suggests that the CaV 2.2 amino terminal and I–II loop contribute molecular determinants for Ca2+ channel function; the data favour a direct interaction of peptides with Ca2+ channels to inhibit synaptic transmission and attenuate G protein modulation. Non-technical summary: Nerve cells (neurones) in the body communicate with each other by releasing chemicals (neurotransmitters) which act on proteins called receptors. An important group of receptors (called G protein coupled receptors, GPCRs) regulate the release of neurotransmitters by an action on the ion channels that let calcium into the cell. Here, we show for the first time that small peptides based on specific regions of calcium ion channels involved in GPCR signalling can themselves inhibit nerve cell communication. We show that these peptides act directly on calcium channels to make them more difficult to open and thus reduce calcium influx into native neurones. These peptides also reduce GPCR-mediated signalling. This work is important in increasing our knowledge about modulation of the calcium ion channel protein; such knowledge may help in the development of drugs to prevent signalling in pathways such as those involved in pain perception

Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice.

BackgroundKetamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice.MethodsIn the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice.ResultsRestoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating.ConclusionsOur studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion

Aisha Bano - The Role of KCNQ (Kv7) Potassium Channels in Schizophrenia Deficits

For years, studies have been conducted to treat the positive and negative symptoms and cognitive deficits of schizophrenia; it has allowed to treat the positive symptoms through regulation of dopaminergic neurons and dopamine pathways; however, we still do not know how to treat the negative symptoms and cognitive deficits. The reason we cannot treat them is due to a lack of adequate understanding of the underlying pathology which manifests itself in the behavior. Over the years, there have been multiple proposed hypotheses regarding the underlying pathology, and accordingly, medication were developed to regulate the variety of pathways in the brain but each of them has failed. Under the mentorship of Dr. Behnam Ghasemzadeh, experiments are being conducted to regulate the activity of KCNQ potassium ion channel to ameliorate the negative symptoms and cognitive deficits of schizophrenia. The experiments are being conducted using animal-models of schizophrenia like-effect. The results suggest that decrease in the activity of the KCNQ potassium channels, leading to an increase in the neuronal activity, may be able to treat the symptoms of schizophrenia.https://epublications.marquette.edu/mcnair_2013/1007/thumbnail.jp

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

BackgroundEndophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.MethodsParticipants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.ResultsMost neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.ConclusionsThe majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research

The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2Ccontaining NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK- 801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders