Auditory Gating Research Articles

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1β3γ2 and α5β3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

Gait and Conditioned Fear Impairments in a Mouse Model of Comorbid TBI and PTSD.

Study Objectives Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) commonly cooccur. Approaches to research and treatment of these disorders have been segregated, despite overlapping symptomology. We and others have hypothesized that comorbid TBI + PTSD generates worse symptoms than either condition alone. We present a mouse model of comorbid TBI + PTSD to further explore this condition. Methods A mouse model of TBI + PTSD was generated using the single prolonged stress (SPS) protocol in combination with the controlled cortical impact (CCI) protocol. This resulted in four experimental groups: control, TBI, PTSD, and TBI + PTSD. Behavioral phenotyping included gait analysis, contextual fear conditioning, acoustic startle response, and prepulse inhibition. Results Mice in the TBI + PTSD group showed a significantly impaired gait compared to their counterparts with TBI alone as well as control mice. Mice in the TBI + PTSD group showed significantly impaired contextual fear recall compared to controls. Prepulse inhibition testing revealed intact acoustic startle and auditory sensory gating. Conclusions These results indicate that SPS paired with CCI in mice produces unique behavioral impairments in gait and fear recall that are not present in either condition alone. Further studies are underway to examine additional behavioral, physiological, and pathological phenotypes in this combined model of TBI + PTSD.

Changes in the regional shape and volume of subcortical nuclei in patients with tinnitus comorbid with mild hearing loss.

Tinnitus, the perception of sound without an external source, is a prevalent disease, but its underlying mechanism has not been fully elucidated. Recent studies have suggested the involvement of subcortical nuclei in tinnitus generation. We investigated changes in the local shape and volume of subcortical nuclei in relation to tinnitus. The participants included 53 patients with tinnitus and 52 age- and gender-matched normal controls. Individual 3D T1-weighted structural images were obtained using 3-T magnetic resonance imaging. Surface-based vertex analysis (SVA) was performed with automated segmentation of the bilateral caudate nuclei, putamina, nucleus accumbens, thalami, pallidum, hippocampi, amygdalae, and brainstem. The scalar distances from the mean surface and volumes of 15 nuclei were compared between the tinnitus and control groups and correlated with tinnitus handicap score (THI) and tinnitus duration. SVA revealed regional contractions in the accessory basal and lateral nuclei of the right amygdala and expansions in the left medial and right ventral posterior nuclei and lateral dorsal nucleus of both thalami. The surface distances of the right nucleus accumbens were positively correlated with tinnitus duration, while those of the left nucleus accumbens and left hippocampus were negatively correlated with THI. Regional atrophy of the amygdala may indicate self-modulation of emotional response regulation to diminish tinnitus-related emotional distress. Thalamic regional expansion may signify dysfunctional auditory gating in the thalamus, where inhibition of the tinnitus signal at the thalamus level is disrupted due to abnormal changes in the limbic system, ultimately leading to the tinnitus percept.

Let Us Not Play It by Ear: Auditory Gating and Audiovisual Perception During Rapid Goal-Directed Action

Susceptibility to audiovisual illusions is altered during rapid upper-limb reaching movements. Although, this change in perception appears to be linked to the movement's real-time characteristics, the mechanism for this alteration remains unknown. In this paper, we examined whether this modulation of multisensory perception could be explained by a decrease in auditory perceptual sensitivity. In two protocols, participants were instructed to perform rapid reaches to a visual target and report the number of auditory events (beeps) they perceived. One or 2 brief beeps were presented with either 0, 1, or 2 brief visual flashes at 0, 100, or 200 ms (protocol 1), or 0, 200, or 400 ms (protocol 2) relative to movement onset. The results revealed a significant, stable, decrease in auditory perception when the stimuli were presented during the movement, as compared to after the movement, and no-movement trials. Overall, the findings of this paper suggest that auditory perceptual sensitivity is monotonically reduced as one engages in visually guided goal-directed actions.

Impact of childhood trauma on sensory gating in patients with first-episode schizophrenia

BackgroundChildhood trauma (CT) has been found to contribute to the onset of schizophrenia and auditory sensory gating deficit is a leading endophenotype for schizophrenia. However, the association between the CT and sensory gating in first-episode schizophrenia remains elusive.MethodsFifty-six patients and 49 age and sex-matched healthy controls were assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) for CT and Positive and Negative Syndrome Scale (PANSS) for symptoms severity. Sensory gating was tested using the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS-PPI), and the perceived spatial co-location PPI (PSC-PPI or classical PPI).ResultsComparing with healthy controls, the patients had significantly higher score on sexual abuse (t = 2.729, p < 0.05), lower PSS- PPI, % (ISI = 120 ms and ISI = 60 ms) (t = − 3.089, − 4.196, p < 0.05). Univariate analysis revealed the absence of a significant correlation among CT, PPI paradigms and symptoms. However, multiple linear regression analyses demonstrated the CTQ-SF total was negatively associated with PSS PPI (ISI = 120 ms) (p = 0.018).ConclusionThe current study illustrates that the impact of CT on sensory gating in patients with first-episode schizophrenia, and thus we conclude that CT may be a risk factor to the occurrence of schizophrenia through its impact on sensory gating.

Auditory N100 gating in patients with schizophrenia: A systematic meta-analysis

ObjectiveThe study sought to assess the presence of auditory N100 gating deficits in patients with schizophrenia by meta-analysis. MethodsLiterature was screened for studies on patients with schizophrenia that used the paired-click paradigm and reported N100 data. Both electroencephalographic and magnetoencephalographic studies were considered. N100 gating measures as well as the N100 amplitudes to the initial and repeated stimulus were extracted and subjected to a meta-analysis. ResultsThe literature research revealed 29 studies, reporting either N100 gating or N100 amplitude measures in paired-click experiments. Patients with schizophrenia exhibited less N100 gating than healthy controls across studies (mean g = −0.405, SE = 0.051). However, what appeared as a gating deficit in patients was due to reduced N100 amplitudes to the initial stimulus in this group (mean g = 0.610, SE = 0.075). Patients and controls did not differ in their N100 amplitudes to the repeated stimulus (mean g = 0.042, SE = 0.066). ConclusionThere is no evidence for an auditory N100 gating deficit in schizophrenia, but for an impaired N100 response recovery. SignificancePrevious findings on impaired N100 gating in schizophrenia patients reflect deficient processing of auditory salience rather than defective inhibition of repeating redundant auditory stimulation.

Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer's Disease Pathology.

Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal-cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer's disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal-cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.

COMT and the neurogenetic architecture of hearing loss induced tinnitus

As the COMT polymorphism is especially prominent in the prefrontal cortex and has been associated with auditory gating, we hypothesize that tinnitus patients with this polymorphism have altered activity in the ventromedial prefrontal/anterior cingulate areas that modulates the tinnitus percept. To test this, we recruited a total of 40 tinnitus subjects and 20 healthy controls for an EEG study. A comparison between tinnitus subjects and healthy controls and their frequency of being Val/Val genotype or Met carriers (including Val/Met and Met/Met genotype) shows no significant effect, suggesting that the distributions for the tinnitus and healthy groups are similar. Our results show that an interaction between the amount of hearing loss and the COMT Val158Met polymorphism can increase susceptibility to the clinical manifestation of tinnitus. We further demonstrate that the parahippocampus becomes involved in tinnitus in patients with hearing loss that are Met carriers. In these patients, the parahippocampus sends more tinnitus information to the pregenual anterior cingulate cortex and auditory cortex that is specifically related with increased loudness. At the same time, the pregenual anterior cingulate cortex, which normally functions as a gatekeeper, is not cancelling this auditory information, ultimately leading to increased tinnitus loudness.

Startle habituation, sensory, and sensorimotor gating in trauma-affected refugees with posttraumatic stress disorder.

Impairments in mechanisms underlying early information processing have been reported in posttraumatic stress disorder (PTSD); however, findings in the existing literature are inconsistent. This current study capitalizes on technological advancements of research on electroencephalographic event-related potential and applies it to a novel PTSD population consisting of trauma-affected refugees. A total of 25 trauma-affected refugees with PTSD and 20 healthy refugee controls matched on age, gender, and country of origin completed the study. In two distinct auditory paradigms sensory gating, indexed as P50 suppression, and sensorimotor gating, indexed as prepulse inhibition (PPI), startle reactivity, and habituation of the eye-blink startle response were examined. Within the P50 paradigm, N100 and P200 amplitudes were also assessed. In addition, correlations between psychophysiological and clinical measures were investigated. PTSD patients demonstrated significantly elevated stimuli responses across the two paradigms, reflected in both increased amplitude of the eye-blink startle response, and increased N100 and P200 amplitudes relative to healthy refugee controls. We found a trend toward reduced habituation in the patients, while the groups did not differ in PPI and P50 suppression. Among correlations, we found that eye-blink startle responses were associated with higher overall illness severity and lower levels of functioning. Fundamental gating mechanisms appeared intact, while the pattern of deficits in trauma-affected refugees with PTSD point toward a different form of sensory overload, an overall neural hypersensitivity and disrupted the ability to down-regulate stimuli responses. This study represents an initial step toward elucidating sensory processing deficits in a PTSD subgroup.

Sensory Gating Deficits and their Clinical Correlates in Drug-Free/Drug-Naive Patients with Schizophrenia.

Background:Sensory gating refers to “filtering” of irrelevant sensory input in the brain. Auditory sensory gating deficit has been considered as a marker of schizophrenia (SCZ) and assessed using P50 paired-click paradigm. We explore sensory gating deficits and their clinical correlates in SCZ.Materials and Methods:Twenty-five drug-free/drug-naïve patients with SCZ, whose psychopathology was assessed using Positive and Negative Syndrome Scale (PANSS), and 25 age-matched normal controls (NC) were recruited. ERP recordings were done using 40-channel event-related potential measuring system.Results:S2-S1 P50 amplitude difference, an index of sensory gating, was significantly lower in SCZ at F3 and F4 sites when compared to NC, indicating impaired gating. SCZ had significantly lower S1 amplitude compared to NC at these sites; S2 amplitudes were comparable. The sensory gating index also showed significant correlations with PANSS scores.Conclusions:Our study reiterates sensory gating abnormalities in SCZ and confers a frontal specificity, implying specific deficits in early preattentive processes to them. Further, we suggest that gating deficits in SCZ are driven predominantly by abnormally small S1 rather than an inability to suppress S2. A correlation between sensory gating parameters and measures of psychopathology strengthens the hypothesis that abnormal response to sensory input may contribute to the psychopathology in SCZ.

Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice.

A series of novel thiazolo[4,5- d]pyrimidin-7(6 H)-ones (3aa-3eq) were designed, synthesized, and evaluated as the type I positive allosteric modulators of human α7 nAChR expressed in Xenopus ooctyes by a two-electrode voltage clamp. The structure-activity relationship analysis identified the compound 3ea as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 μM) and an EC50 = 1.26 μM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT3A, NMDA, and GABAA receptors. Compound 3ea showed an elimination half-life of 10.8 ± 1.5 h for 3 mg/kg, i.v., and 7.4 ± 1.1 h for 60 mg/kg, i.g. in rat. It also exhibited sufficient blood-brain barrier penetration with no significant effect on hERG channel. Most importantly, compound 3ea dose-dependently (0.1-1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model.

Pharmacological Properties and Evaluations of a Novel Positive Allosteric Modulator of α7 nAChR for Attenuation of Schizophrenia-Like Behavior in Mice

The alpha-7 neuronal nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca2+-permeable ion channel critical for cognition, sensory processing, attention, and working memory. Dysfunctional α7 nAChR is implicated in cognition and neuropsychiatric disorders. Therefore, enhancement of α7 nAChR function is considered to be therapeutic strategy aimed at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. We recently synthesized a novel series of 6-(2-Chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-ones as positive allosteric modulators (PAM) of α7 nAChR. In this study we evaluated the effect of a representative compound JWX-A0108 on activation of α7 and auditory gating or cognitive deficits in mice using a combination of assays including two-electrode voltage clamp (TEVC) recordings of Xenopus oocytes expressing human α7 nAChR, brain slice recordings, pre-pulse inhibition (PPI) for startle response and Y-maze spontaneous alternation test. Compound JWX-A0108 exhibits as type I PAM that specifically activates α7 current in the presence of 100 µM ACh in dose-dependent manner with EC50 at 5.7 ± 0.7 µM and 6-fold increase of the current. Application of JWX-A0108 (1-10 mg/kg, i.p.) dose-dependently reversed the auditory gating deficit induced by NMDA antagonist MK-801 in prepulse inhibition assay. In Y-maze, JWX-A0108 (0.03-0.3 mg/kg, i.p.) significantly increased the time spent in novel arm from 45% to 63% in mice treated with MK-801. We also evaluated the effect of JWX-A0108 on locomotor activity, and fount that JWX-A0108 (0.03 mg/kg, i.p.) significantly reduced MK-801-induced hyperactivity. The effects of JWX-A0108 on selectivity, pERK signaling and synaptic transmissions are currently being investigated.

Auditory sensory gating predicts acceptable noise level

Auditory sensory gating predicts acceptable noise level

Parasympathetic activation enhanced by slow respiration modulates early auditory sensory gating.

Sensory gating is a preattentional mechanism to filter irrelevant information from the environment. It is typically reflected as a suppression of the event-related P50 component for successive sounds in the auditory modality. Although stress-induced sympathetic activation has been reported to disrupt P50 suppression, little is known about the modulatory effect of parasympathetic activation on early auditory sensory gating. We determined the parasympathetic effect on the magnetic P50 (P50m) suppression by controlling the respiratory rhythm and recording data simultaneously with magnetoencephalography and electrocardiography, using three successive click sounds as stimulus and ten normal individuals as study participants. The respiratory rhythm was guided by visual cues and set at 0.3, 0.25, or 0.2 Hz for distinct auditory stimulus sequence blocks. Heart rate variability analysis showed that slow respiration leads to significantly large high-frequency power, which is known as the parasympathetic index, whereas low-frequency/high-frequency ratio, known as the sympathetic index, did not differ with the respiratory rhythm. Although P50m suppression was observed in the left and right primary auditory areas for every respiratory condition, the left P50m intensity for the first sound was significantly decreased in the case of slow respiration, thereby indicating disruption of the left P50m suppression. Since background alpha oscillatory power, reflecting the arousal level, was similar for every respiratory rhythm, it is concluded that parasympathetic activation enhanced by slow respiration modulates P50m gating by reducing the initial neural sensitivity for an auditory input. Not only sympathetic but also parasympathetic effects should be considered in the evaluation of P50/P50m biomarkers.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Multimodal Neuroimaging in Schizophrenia: Description and Dissemination

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network’s collaborative informatics and neuroimaging suite (COINS).

Medial septum modulates hippocampal gamma activity and prepulse inhibition in an N-methyl-d-aspartate receptor antagonist model of schizophrenia

We reviewed the participation of the septohippocampal system in an animal model of schizophrenia that was acutely induced by systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist such as phencyclidine, MK-801 and ketamine. The NMDA receptor antagonist-induced model of schizophrenia is characterized by behavioral and electrophysiological disruptions, including a decrease in prepulse inhibition of the acoustic startle response (PPI), hyperlocomotion, decrease in gating of hippocampal auditory evoked potentials and robust increase in hippocampal gamma (30–100Hz) oscillations. Similar disruptions were also induced by a single electrographic seizure in the hippocampus. The behavioral and electrophysiological disruptions induced by an NMDA receptor antagonist can be reduced by inactivation or lesion of GABAergic neurons in the medial septum, deep brain stimulation of the medial septum or nucleus accumbens, or positive modulation of GABAB receptors. Our results suggest a close association between high-amplitude hippocampal gamma oscillations and psychosis-relevant behaviors including PPI loss, behavioral hyperactivity and loss in auditory gating. Abnormal electrophysiology suggests a disruption of somatic and apical dendritic inhibition in the hippocampus, resulting in distorted sensory integration, and impaired cognitive and memory processing. The hippocampus is suggested to be a hub in a brain network that participates in psychosis-relevant behaviors, through its direct projection to the nucleus accumbens, or through indirect connections via the entorhinal, cingulate and prefrontal cortices.

MEG biomarker of Alzheimer's disease: Absence of a prefrontal generator during auditory sensory gating.

Magnetoencephalography (MEG), a direct measure of neuronal activity, is an underexplored tool in the search for biomarkers of Alzheimer's disease (AD). In this study, we used MEG source estimates of auditory gating generators, nonlinear correlations with neuropsychological results, and multivariate analyses to examine the sensitivity and specificity of gating topology modulation to detect AD. Our results demonstrated the use of MEG localization of a medial prefrontal (mPFC) gating generator as a discrete (binary) detector of AD at the individual level and resulted in recategorizing the participant categories in: (1) controls with mPFC generator localized in response to both the standard and deviant tones; (2) a possible preclinical stage of AD participants (a lower functioning group of controls) in which mPFC activation was localized to the deviant tone only; and (3) symptomatic AD in which mPFC activation was not localized to either the deviant or standard tones. This approach showed a large effect size (0.9) and high accuracy, sensitivity, and specificity (100%) in identifying symptomatic AD patients within a limited research sample. The present results demonstrate high potential of mPFC activation as a noninvasive biomarker of AD pathology during putative preclinical and clinical stages. Hum Brain Mapp 38:5180-5194, 2017. © 2017 Wiley Periodicals, Inc.

P50 suppression deficits and psychopathology in Han Chinese patients with schizophrenia.

Numerous studies have reported P50 gating deficits in schizophrenia, though with mixed results. Moreover, few studies have explored the association between P50 gating deficits and psychopathology in Chinese patients with schizophrenia. In the present study, we investigated the P50 auditory sensory gating patterns and their correlations with clinical symptoms in a large sample of Han Chinese patients with schizophrenia. We assessed P50 sensory gating with a 64-channel electroencephalography system in 133 patients with schizophrenia and 148 healthy controls. The schizophrenia symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS). Patients with schizophrenia had a significantly higher P50 gating ratio (p<0.001), longer S1 latency (p<0.05), lower S1 amplitude (p<0.01), and lower P50 difference (p<0.001) than did controls. No significant correlations were found between the P50 gating measures and the PANSS total score or subscale scores in patients with schizophrenia. These findings suggest that the P50 sensory gating deficits identified in Chinese patients with schizophrenia may not be involved in the psychopathology of the illness.

Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents

The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.