Prepulse Inhibition Deficits Research Articles

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

Maternal Immune Activation in Mice Only Partially Recapitulates the Autism Spectrum Disorders Symptomatology

Prenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. In both sexes high levels of repetitive motor responses and sensory gating deficits in PPI were the more striking effects of Poly I:C, whereas no alteration of social responses were evidenced. Poly I:C treatment did not affect mean values, but, intriguingly, increased variability in the levels of four aminoacids (aspartate glycine and GABA) selectively in males. As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatology.

T39. IMPAIRED SENSORIMOTOR GATING USING THE ACOUSTIC PREPULSE INHIBITION PARADIGM IN INDIVIDUALS AT A CLINICAL HIGH RISK FOR PSYCHOSIS

BackgroundMany robust studies on prepulse inhibition (PPI) were conducted in patients with schizophrenia, and, increasingly, evidence has indicated individuals who are at clinical high risk for psychosis (CHR). The specificity of the PPI is insufficient with the classic paradigm. The current study investigated an improved perceived spatial separation PPI (PSSPPI) paradigm in CHR individuals, compared with patients of first-episode schizophrenia (FES) and healthy controls (HC), and the relationship between PPI, demographics, clinical characteristics, and cognitive performance.MethodsWe included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes (SIPS). The prepulse inhibition measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI paradigms were applied using 60- and 120-ms lead intervals. The MATRICS Consensus Cognitive Battery (MCCB) was used to assess neurocognitive functions.ResultsCompared with HC, the CHR group had lower PSSPPI level (ISI=60 ms, P<0.001; ISI=120 ms, P<.001). PSSPPI showed a large effect size (ES) between CHR and HC (ISI=60 ms, ES=0.91; ISI=120 ms, ES=0.98); on PSSPPI using 60-ms lead interval, ES ranged from small to large from CHR to FES. PPI deficits in CHR were unrelated to demographics, clinical characteristics, and cognition.DiscussionCHR individuals show a sensorimotor gating deficit similar to FES patients on PSSPPI of the startle response, with greater sensitivity than the classic PPI paradigm. PSSPPI appears a promising objective approach for identifying individuals at clinical high risk for psychosis related to a high risk of transition to schizophrenia.

T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS

BackgroundSchizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical roles in the mediation of many neurodevelopmental processes, and, when disturbed, may also contribute to the precipitation of psychiatric disorders, such as SCZ. While a handful of candidate-based studies have measured changes in promoter-bound histone modifications, few mechanistic studies have been carried out to explore how these modifications may affect chromatin to precipitate behavioral phenotypes associated with the disease.MethodsWe applied an unbiased proteomics approach to evaluate the epigenetic landscape of SCZ in human induced pluripotent stem cells (hiPSC), neural progenitor cells (NPCs) and neurons from SCZ patients vs. matched controls. We utilized proteomics-based, label free liquid chromatography mass spectrometry (LC-MS/MS) on purified histones from these cells and confirmed our results by western blotting in postmortem SCZ cortical brain tissues. Furthermore we validated our findings with the application of histone interaction assays and structural and biophysical assessments to identify and confirm novel chromatin ‘readers’. To relate our findings to a SCZ phenotype we used a SCZ rodent model of prepulse inhibition (PPI) to perform pharmacological manipulations and behavioral assessments.ResultsUsing label free mass spectrometry we performed PTM screening of hiPSCs, NPCs and matured neurons derived from SCZ patients and matched controls. We identified, amongst others, altered patterns of hyperacetylation in SCZ neurons. Additionally we identified enhanced binding of particular acetylation ‘reader’ proteins. Pharmacological inhibition of such proteins in an animal model of amphetamine sensitization ameliorated PPI deficits further validating this epigenetic signature in SCZ.DiscussionRecent evidence indicates that relevance and patterns of acetylation in epigenetics advances beyond its role in transcription and small molecule inhibitors of these aberrant interactions hold promise as useful therapeutics. This study identifies a role for modulating gene expression changes associated with a SCZ epigenetic signature and warrants further investigation in terms of how this early gene expression pattern perhaps determines susceptibility or severity of the SCZ disease trajectory.

Enhancing excitatory projections from the ventral subiculum to the nucleus accumbens shell contribute to the MK-801-induced impairment of prepulse inhibition

Prepulse inhibition (PPI), a measure of sensorimotor gating, has been shown to be disrupted in several animal models of neuropsychiatric disorders, such as schizophrenia. The neural circuits involving the hippocampus and nucleus accumbens (NAC) have been studied in rats to uncover the neurochemical and neuroanatomical substrates that regulate PPI. Majority of the studies of the hippocampus on PPI to date have been focused on CA1, CA2, and dentate gyrus (DG) area. Little is known about the role of the subiculum, which maintains the hippocampal formation intact, on the sensorimotor gating. In this study, the PPI disruption was induced by intraperitoneal injection of MK-801 in rats, and the neuronal activity in the dorsal and ventral subiculum by c-Fos immunostaining was examined. The projections from the subiculum to the nucleus accumbens (NAC) were detected by retrograde tracing of cholera toxin B subunit, in the PPI dysfunctional animals. The results showed an increase in neuronal activity in the ventral subiculum (vSub) while remaining constant in the dorsal subiculum during PPI disruption. The excitatory projections from the vSub to the NAC shell were significantly enhanced when PPI was disrupted. Muscimol Inhibition of vSub could significantly ameliorate the MK801-induced PPI deficit. This data suggests that the enhancement of neuronal activity in the vSub was associated with the PPI impairment, possibly due to the enhanced excitatory output from vSub the NAC shell.

Elucidation of the purinergic P2X4‐dopamine receptor interaction in regulation of sensorimotor gating and underlying signaling molecules

Purinergic P2X4 receptors (P2X4Rs) are ion channels gated by adenosine‐5′‐triphosphate in the brain. Recent investigations from our laboratory have reported a role for P2X4Rs in regulation of various behaviors including sensorimotor gating, emotional responses to acute stressors, motor behavior and drug reward. Amongst these behaviors, our laboratory was greatly interested in the role of P2X4Rs in regulation of sensorimotor gating considering that disruption of this function has major implications in wide spectrum of psychiatric disorders including schizophrenia, bipolar disorder and autism. Sensorimotor gating is the process by which irrelevant stimuli can be filtered out prior to generation of motor output in response to a sensory stimulus. This process allows an individual to efficiently navigate a stimulus‐laden environment with minimum distraction. Positive modulation of P2X4Rs by ivermectin (IVM) induced deficits in prepulse inhibition (PPI) of acoustic startle reflex, which is a reliable operational measure for sensorimotor gating. Additionally mice deficient in the p2rx4 gene [i.e. (P2X4R KO)] exhibited PPI deficits in comparison to the wildtype (WT) littermates. Interestingly, the PPI deficits in P2X4R KO mice were rescued by DA receptor antagonists indicating an interaction between P2X4Rs and DA receptors in PPI regulation. On the basis of findings from P2X4R KO mouse model, we hypothesized that modulation of DA receptors can regulate the effects of IVM on PPI. This was accomplished by testing the effects of DA receptor antagonists, SCH 23390 (for D1 receptors) (1mg/kg) and raclopride (for D2 receptors) (3 mg/kg) on IVM‐mediated PPI deficits. We also tested the effects of DA receptor agonists, SKF 82958 (for D1 receptors) (0.1mg/kg) and quinpirole (for D2 receptors) (0.1 mg/kg) on IVM‐mediated changes in behavior. To elucidate the mechanisms underlying the behavioral outcomes, we investigated the interaction between IVM and dopaminergic drugs on phosphorylation of signaling molecules linked to PPI including dopamine and cyclic‐AMP regulated phosphoprotein of 32kDa (DARPP‐32), Ca2+/calmodulin kinase II (CaMKII), neuronal nitric oxide synthase (nNOS) and secondary messengers such as guanosine‐3′,5′‐cyclic monophosphate(cGMP) in the ventral striatum . We found that SCH 23390 significantly attenuated the PPI disruptive effects of IVM to a much greater degree than raclopride. On the contrary, quinpirole, but not SKF 82958, potentiated IVM‐mediated PPI disruption. At the molecular level, SCH 23390 and raclopride significantly blocked IVM‐mediated changes in phosphorylation of all the signaling molecules in the ventral striatum. SKF 82958 significantly potentiated IVM’s effects on DARPP‐32 and CaMKIIα phosphorylation in the same brain region. Overall, these findings suggest that pharmacological activation of P2X4Rs can induce dysregulation of signaling cascades downstream of DA receptors which can result in PPI deficits. Finally, these findings represent P2X4Rs as a novel drug target for treatment of disorders with inherent DA dysfunction that can consequentially lead to sensorimotor gating perturbations.Support or Funding InformationNIAAA/NIH AA0224488 (D.L.D)IVM disrupted PPI function that was significantly reversed by SCH 23390 and raclopride (A). Neither of the DA receptor antagonists significantly impacted IVM‐mediated effects on startle magnitude (B). Values represent mean PPI % or startle amplitude ± SEM from 18–22 mice per treatment group. ***P &lt;0.001 versus control group. #P&lt;0.05, ##P&lt;0.01 versus IVM‐treated mice. +++P&lt;0.001 versus SCH 23390‐treated mice and $P&lt;0.05 versus raclopride‐treated mice, Tukey’s multiple comparison test.Figure 1IVM modulated DARPP‐32 phosphorylation via P2X4R potentiation in a D1 receptor‐dependent manner in the ventral striatum. Inter‐dependence between P2X4Rs and D1 receptors in DARPP‐32 phosphorylation may be relevant to DA‐dependent behaviors such as sensorimotor gating (A). The ability of raclopride to block IVM‐mediated changes at behavioral and cellular level indicates a plausible interaction between P2X4Rs and D2 receptors in regulation of DA‐dependent behaviors and signaling pathways (B).Figure 2

Estimating the causal effect of prenatal lead exposure on prepulse inhibition deficits in children and adolescents

During pregnancy, maternal lead from earlier exposures mobilizes and crosses placental barriers, placing the developing fetus at risk for lead exposure and neurodevelopmental deficits. Some neuronal circuits known to be affected in neurodevelopment disorders can be probed with simple physiological behavioral paradigms. One such neural biomarker is Pre-Pulse Inhibition (PPI), an indicator of adequate sensorimotor gating processing. In clinical studies, deficits in PPI have been associated with neurodevelopmental disorders in human subjects. To our knowledge, no studies have examined the use of PPI as a biomarker of toxicant effects on the brain in epidemiological studies. We aimed to estimate the causal effect of prenatal lead exposure, assessed by maternal cortical bone lead concentrations, on PPI in 279 children from Mexico City. in vivo maternal cortical bone lead measurements were taken at four weeks postpartum at the mid-tibia shaft using a K-Shell X-ray fluorescence instrument. PPI recording occurred in an isolated clinical setting and eye blink responses were measured using electromyography. We assessed if the conditions for causal inference held in our study and used the results of our assessment to estimate the causal effect of prenatal lead exposure on PPI using an ordinary least squares regression model, a marginal structural model, and the parametric g-formula. Results were consistent across the three modeling approaches. For the parametric g-formula, a one standard deviation (10.0 μg/g) increase in prenatal lead significantly reduced PPI by approximately 19.0 % (95 % CI: 5.4 %, 34.3 %). This decrease is similar in magnitude to clinical studies on schizophrenia, which have observed PPI impairments in patients with schizophrenia as compared to controls. Our results are consistent with findings from other studies establishing an association between lead exposure and neurodevelopmental disorders in children and suggest that PPI may be useful as an objective biomarker of toxicant effects on the brain.

Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.

Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.

The Impact of Removal of Ovarian Hormones on Cholinergic Muscarinic Receptors: Examining Prepulse Inhibition and Receptor Binding.

Ovarian hormones, such as estrogens and progesterone, are known to exert beneficial effects on cognition and some psychiatric disorders. The basis of these effects is not fully understood, but may involve altered cholinergic neurotransmission. This study aimed to investigate how a lack of ovarian hormones would impact muscarinic receptor-induced deficits in prepulse inhibition (PPI) and muscarinic receptor density in several brain regions. Adult female rats were either ovariectomized, to remove the source of ovarian hormones, or left intact (sham-operated). PPI is a measure of sensorimotor gating that is typically impaired in schizophrenia patients, and similar deficits can be induced in rats by administering scopolamine, a muscarinic receptor antagonist. Our results revealed no significant effects of ovariectomy on PPI after saline or scopolamine treatment. Autoradiography was performed to measure cholinergic muscarinic receptor binding density using [3H]-pirenzepine, [3H]-AF-DX, and [3H]-4-DAMP, to label M1, M2/M4, and M3 receptors, respectively. We examined the amygdala, caudate putamen, dorsal hippocampus, motor cortex, retrosplenial cortex, and ventromedial hypothalamus. There were no significant group differences in any region for any muscarinic receptor type. These results suggest that removing peripheral ovarian hormones does not influence the cholinergic muscarinic receptor system in the context of PPI or receptor binding density.

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.

Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats

Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments.

Ketamine induces immediate and delayed alterations of OCD-like behavior.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by intrusive obsessive thoughts and/or compulsive behaviors. Currently, serotonin reuptake inhibitors (SRIs) provide the only pharmacological monotherapy for OCD, but response rates are insufficient. Ketamine, a noncompetitive NMDA receptor antagonist, was reported to have rapid, sustained therapeutic effects in OCD patients. However, the mechanisms remain unknown. Here, we aimed to provide a platform for investigating mechanisms underlying anti-OCD effects of ketamine treatment by assessing whether ketamine pretreatment could alleviate 5-HT1B receptor (5-HT1BR)-induced OCD-like behavior in mice. We assessed whether acute ketamine (0, 3, 10, 30 mg/kg), administered at two pretreatment time points (30 min, 24 h), would modulate 5-HT1BR-induced OCD-like behavior in mice. Behavioral measures were perseverative hyperlocomotion in the open field and deficits in prepulse inhibition (PPI) induced by acute pharmacological 5-HT1BR challenge. Three milligrams per kilogram of ketamine reduced 5-HT1BR-induced perseverative hyperlocomotion, but not PPI deficits, 24 h postinjection. In contrast, higher doses of ketamine were either ineffective (10 mg/kg) or exacerbated (30 mg/kg) 5-HT1BR-induced perseverative hyperlocomotion 30 min postinjection. At 24 h postinjection, 30 mg/kg ketamine reduced perseverative hyperlocomotion across all groups. Our results suggest that the 5-HT1BR-induced model of OCD-like behavior is sensitive to a low dose of ketamine, a potential fast-acting anti-OCD treatment, and may provide a tool for studying mechanisms underlying the rapid therapeutic effects of ketamine in OCD patients.

The comparative study of the early stages of sensory and sensory-motor information processing in aggressive and non-aggressive schizophrenic patients

To study the early stages of sensory (P50 suppression) and sensorimotor (prepulse modification of acoustic startle reaction - ASR) information processing in aggressive and non-aggressive patients with schizophrenia. Two groups (aggressive group A, 44 s. and non-aggressive group NA, 27 s.) and 48 healthy people were studied using oculography and encephalography. Symptoms of schizophrenia were assessed by PANSS. The analysis of ASR and P50 revealed the increased ASR latency, deficit of prepulse inhibition (PPI) with 60 ms leading interval, and P50 suppression in patients compared to controls. Aggressive behavior impacted on lateral features of ASR changes in the group A. The increase of ASR amplitude and the decline of prepulse facilitation were found in the group NA. The P50 analysis revealed the increased P50 amplitude and the shortened latency in response to 2nd stimulus in the pair. The increase in scores on item G14 of the PANSS (Poor impulse control) in the group A and its correlations with ASR and P50 parameters in this group suggested the important role of impulsivity in aggressive behavior in the studied sample of aggressive patients. ASR and P50 characteristics in the group NA are associated with increased sensitivity to incoming stimuli and such personality traits as increased alertness and fear, which might inhibit aggression. Thus, indicators of the early stages of information processing can be considered as potential predictors of aggressive behavior.

Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model.

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

Deciphering midbrain mechanisms underlying prepulse inhibition of startle

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a hallmark of schizophrenia and associated with several other psychiatric illnesses such as e.g. autism spectrum disorder, yet the mechanisms underlying PPI are still not fully understood. There is growing evidence contradicting the long-standing hypothesis that PPI is mediated by a short feed-forward midbrain circuitry including inhibitory cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the startle pathway. Here, we employed a chemogenetic approach to explore the involvement of the PPTg in general, and cholinergic neurons specifically, in PPI. Activation of inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in the PPTg by systemic administration of clozapine-N-oxide (CNO) disrupted PPI, confirming the involvement of the PPTg in PPI. In contrast, chemogenetic inhibition of specifically cholinergic PPTg neurons had no effect on PPI, but inhibited morphine-induced conditioned place preference (CPP) in the same animals, showing that the DREADDs were effective in modulating behavior. These findings support a functional role of the PPTg and/or neighboring structures in PPI in accordance with previous lesion studies, but also provide strong evidence against the hypothesis that specifically cholinergic PPTg neurons are involved in mediating PPI, implicating rather non-cholinergic midbrain neurons.

A Cross-Species Systems Genetics Analysis Links APBB1IP as a Candidate for Schizophrenia and Prepulse Inhibition.

Background: Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives. PPI can be measured in many species, and shows considerable phenotypic variation between and within rodent models. This makes PPI a useful endophenotype. Genome-wide association studies (GWAS) have been carried out to identify genetic variants underlying schizophrenia, and these suggest that schizophrenia is highly polygenic. GWAS have been unable to account for the high heritability of schizophrenia seen in family studies, partly because of the low power of GWAS due to multiple comparisons. By contrast, complementary mouse model linkage studies often have high statistical power to detect variants for behavioral traits but lower resolution, producing loci that include tens or hundreds of genes. To capitalize on the advantages of both GWAS and genetic mouse models, our study uses a cross-species approach to identify novel genes associated with PPI regulation, which thus may contribute to the PPI deficits seen in schizophrenia.Results: Using experimental data from the recombinant inbred (RI) mouse panel BXD, we identified two significant loci affecting PPI. These genomic regions contain genetic variants which influence PPI in mice and are therefore candidates that may be influencing aspects of schizophrenia in humans. We next investigated these regions in whole-genome data from the Psychiatric Genomics Consortium (PGC) schizophrenia GWAS and identify one novel candidate gene (ABPP1IP) that was significantly associated with PPI in mice and risk of schizophrenia in humans. A systems genetics approach demonstrates that APBB1IP coexpresses with several other genes related to schizophrenia in several brain regions. Gene coexpression and enrichment analysis shows clear links between APBB1IP and the immune system.Conclusion: The combination of human GWAS and mouse quantitative trait loci (QTL) from some of the largest study systems available has enabled us to identify a novel gene, APBB1IP, which influences schizophrenia in humans and PPI in mice.

MDGA1-deficiency attenuates prepulse inhibition with alterations of dopamine and serotonin metabolism: An ex vivo HPLC-ECD analysis

MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor) has recently been linked to schizophrenia and bipolar disorder. Dysregulation of dopamine (DA) and serotonin (5-HT) systems has long been associated with schizophrenia and other neuropsychiatric disorders. Here, we measured prepulse inhibition (PPI) of the startle response and ex vivo tissue content of monoamines and their metabolites in the frontal cortex, striatum and hippocampus of Mdga1 homozygous (Mdga1-KO), Mdga1 heterozygous (Mdga1-HT) and wild-type (WT) male mice. We found that Mdga1-KO mice exhibited statistically significant impairment of PPI, and had higher levels of homovanillic acid in all three brain regions studied compared with Mdga1-HT and WT mice (P < 0.05), while levels of norepinephrine, DA and its metabolites 3,4-dihydroxyphenylacetic acid and 3-methoxytyramine remained unchanged. Mdga1-KO mice also had a lower 5-hydroxyindoleacetic acid level in the striatum (P < 0.05) compared with WT mice. 5-HT levels remained unchanged with the exception of a significant increase in the level in the cortex. These data are the first evidence suggesting that MDGA1 deficiency leads to a pronounced deficit in PPI and plays an important role in perturbation of DA and 5-HT metabolism in mouse brain; such changes may contribute to a range of neuropsychiatric disorders.

Defective neurogenesis and schizophrenia-like behavior in PARP-1-deficient mice

In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.

Simultaneous activation of mGlu2 and muscarinic receptors reverses MK-801-induced cognitive decline in rodents

The activity of an allosteric agonist of muscarinic M1 receptor, VU0357017, and a positive allosteric modulator (PAM) of M5 receptor, VU0238429, were investigated alone or in combination with the mGlu2 receptor PAM, LY487379 using the following behavioural tests: prepulse inhibition (PPI), novel object recognition (NOR), and spatial delayed alternation (SDA). VU0357017 (10 and 20 mg/kg) and VU0238429 (5 and 10 mg/kg) reversed deficits in PPI while VU0238429 (2.5 and 5 mg/kg) was effective in SDA. The simultaneous administration of subeffective doses of M1 or M5 activators (5, 1, or 0.25 mg/kg) with LY487379 (0.5 mg/kg) induced the same effect as that observed for the active dose of each compound. Selective M1 or M5 receptor blockers antagonized the effect exerted by these combinations, and pharmacokinetic studies confirmed independent transport through the blood-brain barrier. The expression of both receptors (M1 and M5) was established in brain structures involved in cognition (neocortex, hippocampus, and entorhinal cortex) in both the rat and the mouse brains by immunofluorescence staining. Specifically, double neuronal staining of mGlu2-M1 and mGlu2-M5 receptors was observed in many areas of the rat brain, while the number of double-stained mGlu2-M1 receptors was moderate in the mouse brain with no mGlu2-M5 colocalization. Finally, the combined administration of subeffective doses of the compounds did not alter prolactin levels or motor coordination, in contrast to the compounds given alone at the highest dose or in combination with standard neuroleptics.

A Prospective Study of Methylmercury Exposure and Prepulse Inhibition Deficits in Children and Adolescents

OPS 38: Effects of metals on child health, Room 114, Floor 1, August 27, 2019, 4:30 PM - 5:30 PM Background: Methylmercury (MeHg) exposure has been associated with severe and subtle neurodevelopmental deficits, especially in children. Pre-Pulse Inhibition (PPI), an indicator of adequate sensorimotor gating processing is a neurological biomarker that may be useful for identifying neurodevelopmental deficits earlier and more objectively than behavioral ratings. Furthermore, PPI may be more cost-effective than current brain imaging techniques for assessing the effects of neurotoxicants such as MeHg. Objective: This study examined the association between MeHg exposure and PPI deficits in a prospective cohort of children and adolescents from Mexico City. Methods: We obtained venous whole blood samples and scalp hair samples at two time points from 176 offspring from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort; the PPI evaluation was completed at the second time point, approximately 18 months after the first time point. PPI recording and analysis occurred in an isolated clinical setting and eye blink responses were assessed using electromyography. We used ordinary least squares regression models adjusted for maternal education, maternal IQ, birthweight, child’s sex, and child’s age (predictors of PPI and MeHg) to assess the relationship between earlier and concurrent MeHg concentrations on PPI deficits. Results: The spearman correlation coefficient for blood- and hair-MeHg levels was 0.68 (p < .0001) and 0.73 (p < .0001) at the two visits, respectively. In adjusted models, one µg/L increase in earlier blood-MeHg concentrations was significantly associated with a 0.22 point decrease in PPI (95% CI: 0.07, 0.37). We observed no associations between concurrent blood-MeHg, hair-MeHg concentrations and PPI deficits. Conclusions: In our study population, blood-MeHg concentrations were associated with PPI deficits, which is consistent with MeHg’s known neurotoxicity. Our results underscore the potential utility of PPI as an objective and cost-effective adjunct screening tool for assessing neurotoxicant effects on the brain.