Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Deciphering the role of brainstem glycinergic neurons during startle and prepulse inhibition.

Prepulse inhibition (PPI) of the auditory startle response, a key measure of sensorimotor gating, diminishes with age and is impaired in various neurological conditions. While PPI deficits are often associated with cognitive impairments, their reversal is routinely used in experimental systems for antipsychotic drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. We recently showed that brainstem neurons located in the caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2±) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI but via an uncharted pathway. Here, using tract-tracing, immunohistochemistry and in vitro optogenetic manipulations coupled to field electrophysiological recordings, we reveal the neuroanatomical distribution of GlyT2± PnC neurons and PnC-projecting CeA glutamatergic neurons and we provide mechanistic insights on how these glutamatergic inputs suppress auditory neurotransmission in PnC sections. Additionally, in vivo experiments using GlyT2-Cre mice confirm that optogenetic activation of GlyT2± PnC neurons enhances PPI and is sufficient to induce PPI in young mice, emphasizing their role. However, in older mice, PPI decline is not further influenced by inhibiting GlyT2± neurons. This study highlights the importance of GlyT2± PnC neurons in PPI and underscores their diminished activity in age-related PPI decline.

SKF82958, a dopamine D1 receptor agonist, disrupts prepulse inhibition in the medial prefrontal cortex and nucleus accumbens in C57BL/6J mice.

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.

Disruption of NMDA receptor-mediated regulation of PPI in the maternal immune activation model of schizophrenia is restored by 17ß-estradiol and raloxifene.

Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17ß-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17ß-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17ß-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia.

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Effects of acute and chronic methylphenidate on prepulse inhibition: A sex difference study in Wistar rats.

BACKGROUND: The utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. METHODS: Animals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. RESULTS: Results indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). CONCLUSIONS: These findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.

Baseline prepulse inhibition dependency of orexin A and REM sleep deprivation.

RATIONALE: Prepulse inhibition (PPI) impairment reflects sensorimotor gating problems, i.e. in schizophrenia. This study aims to enlighten the role of orexinergic regulation on PPI in a psychosis-like model. OBJECTIVES: In order to understand the impact of orexinergic innervation on PPI and how it is modulated by age and baseline PPI (bPPI), chronic orexin A (OXA) injections was carried on non-sleep-deprived and sleep-deprived rats that are grouped by their bPPI. METHODS: bPPI measurements were carried on male Wistar rats on P45 or P90 followed by grouping into low-PPI and high-PPI rats. The rats were injected with OXA twice per day for four consecutive days starting on P49 or P94, while the control groups received saline injections. 72 h REMSD was carried on via modified multiple platform technique on P94 and either OXA or saline was injected during REMSD. PPI tests were carried out 30 min. after the last injection. RESULTS: Our previous study with acute OXA injection after REMSD without bPPI grouping revealed that low OXA doses might improve REMSD-induced PPI impairment. Our current results present three important conclusions: (1) The effect of OXA on PPI is bPPI-dependent and age-dependent. (2) The effect of REMSD is bPPI-dependent. (3) The effect of OXA on PPI after REMSD also depends on bPPI. CONCLUSION: Orexinergic regulation of PPI response with and without REMSD can be predicted by bPPI levels. Our findings provide potential insights into the regulation of sensorimotor gating by sleep/wakefulness systems and present potential therapeutic targets for the disorders, where PPI is disturbed.

Prepulse inhibition and the call alert in emergency medical services.

In emergency medical services, paramedics are informed of an emergency call by a high-intensity acoustic alarm called the "call alert." Sudden, loud sounds like the call alert may cause a startle response and be experienced as aversive. Studies have identified an association between the call alert and adverse health effects in first responders; conceivably, these adverse health effects might be reduced by modifying the call alert to blunt its startling and aversive properties. Here, we assessed whether the call alert causes a startle response and whether its startling and aversive properties are reduced when the call alert is preceded by a weak acoustic "prepulse," a process referred to as "prepulse inhibition" (PPI). Paramedics (n = 50; 34M:13F:3 not reported; ages 20-68) were exposed to four call alerts (two with and two without a prepulse) in counterbalanced order. Responses were measured using electromyography (measuring blink amplitude), visual analog scales (quantifying perceived call alert intensity and aversiveness), and an electrocardiogram (assessing heart rate). Paramedics responded to the call alert with a startle reflex blink and an increased heart rate. Acoustic prepulses significantly reduced the amplitude of the call alert-induced startle blink, the perceived sound intensity, and the perceived "dislike" of the call alert. These findings confirm that the call alert is associated with an acoustic startle response in paramedics; adding a prepulse to the call alert can reduce its startling and aversive properties. Conceivably, such reductions might also diminish adverse health effects associated with the call alert in first responders.

Different levels of prepulse inhibition among patients with first-episode schizophrenia, bipolar disorder and major depressive disorder.

BACKGROUND: Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. METHODS: We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). RESULTS: We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. LIMITATIONS: The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. CONCLUSION: The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

Inversed Effects of Nav1.2 Deficiency at Medial Prefrontal Cortex and Ventral Tegmental Area for Prepulse Inhibition in Acoustic Startle Response.

Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric disorders including schizophrenia. However, pathological mechanisms for the schizophrenia-relevant behavioral abnormalities caused by the variants remain poorly understood. Here in this study, we characterized mouse lines with selective Scn2a deletion at schizophrenia-related brain regions, medial prefrontal cortex (mPFC) or ventral tegmental area (VTA), obtained by injecting adeno-associated viruses (AAV) expressing Cre recombinase into homozygous Scn2a-floxed (Scn2afl/fl) mice, in which expression of the Scn2a was locally deleted in the presence of Cre recombinase. The mice lacking Scn2a in the mPFC exhibited a tendency for a reduction in prepulse inhibition (PPI) in acoustic startle response. Conversely, the mice lacking Scn2a in the VTA showed a significant increase in PPI. We also found that the mice lacking Scn2a in the mPFC displayed increased sociability, decreased locomotor activity, and increased anxiety-like behavior, while the mice lacking Scn2a in the VTA did not show any other abnormalities in these parameters except for vertical activity which is one of locomotor activities. These results suggest that Scn2a-deficiencies in mPFC and VTA are inversely relevant for the schizophrenic phenotypes in patients with SCN2A variants.

Schizophrenia-relevant social, attentional and cognitive traits in female RHA vs. RLA rats: Effects of neonatal handling.

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.

Testing Prepulse Inhibition of Acoustic Startle in Rodents.

Prepulse inhibition (PPI) is a measure of sensorimotor gating which is widely used in rodents to study information processing and attention dysfunction. PPI is commonly measured in rats and mice using automated equipment. Here, we present details of a PPI testing protocol extensively used in previous studies. The protocol includes a set pulse-alone startle level and prepulse-pulse combinations with varying interval and intensity. Variations of this protocol can be used depending on the experimental aim or equipment and software version.

Acute ketamine induces neuronal hyperexcitability and deficits in prepulse inhibition by upregulating IL-6.

Acute ketamine administration results in psychotic symptoms similar to those observed in schizophrenia and is regarded as a pharmacological model of schizophrenia. Accumulating evidence suggests that patients with schizophrenia show increased IL-6 levels in the blood and cerebrospinal fluid and that IL-6 levels are associated with the severity of psychotic symptoms. In the present study, we found that a single ketamine exposure led to increased expression of IL-6 and IL-6Rα, decreased dendritic spine density, increased expression and currents of T-type calcium channels, and increased neuron excitability in the hippocampal CA1 area 12 h after exposure. Acute ketamine administration also led to impaired prepulse inhibition (PPI) 12 h after administration. Additionally, we found that the expression of signaling molecules IKKα/ß, NF-κB, JAK2, and STAT3 was upregulated 12 h after a single ketamine injection. The decreases in dendritic spine density, the increases in calcium currents and neuron excitability, and the impairments in PPI were ameliorated by blocking IL-6 or IL-6Rα. Our findings show that blocking IL-6 or its receptor may protect hippocampal neurons from hyperexcitability, thereby ameliorating ketamine-induced psychotic effects. Our study provides additional evidence that targeting IL-6 and its receptor is a potential strategy for treating psychotic symptoms in acute ketamine-induced psychosis and schizophrenia.

Accessible and reliable neurometric testing in humans using a smartphone platform.

Tests of human brain circuit function typically require fixed equipment in lab environments. We have developed a smartphone-based platform for neurometric testing. This platform, which uses AI models like computer vision, is optimized for at-home use and produces reproducible, robust results on a battery of tests, including eyeblink conditioning, prepulse inhibition of acoustic startle response, and startle habituation. This approach provides a scalable, universal resource for quantitative assays of central nervous system function.

Assessing the Cntnap2 knockout rat prepulse inhibition deficit through prepulse scaling of the baseline startle response curve.

Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.

N1-P2 event-related potentials and perceived intensity are associated: The effects of a weak pre-stimulus and attentional load on processing of a subsequent intense stimulus.

A weak stimulus presented immediately before a more intense one reduces both the N1-P2 cortical response and the perceived intensity of the intense stimulus. The former effect is referred to as cortical prepulse inhibition (PPI), the latter as prepulse inhibition of perceived stimulus intensity (PPIPSI). Both phenomena are used to study sensory gating in clinical and non-clinical populations, however little is known about their relationship. Here, we investigated 1) the possibility that cortical PPI and PPIPSI are associated, and 2) how they are affected by attentional load. Participants were tasked with comparing the intensity of an electric pulse presented alone versus one preceded 200 ms by a weaker electric prepulse (Experiment 1), or an acoustic pulse presented alone with one preceded 170 ms by a weaker acoustic prepulse (Experiment 2). A counting task (easy vs. hard) manipulating attentional load was included in Experiment 2. In both experiments, we observed a relationship between N1-P2 amplitude and perceived intensity, where greater cortical PPI was associated with a higher probability of perceiving the 'pulse with prepulse' as less intense. Moreover, higher attentional load decreased observations of PPIPSI but had no effect on N1-P2 amplitude. Based on the findings we propose that PPIPSI partially relies on the allocation of attentional resources towards monitoring cortical channels that process stimulus intensity characteristics such as the N1-P2 complex.

Sprague Dawley rats from different vendors vary in the modulation of prepulse inhibition of startle (PPI) by dopamine, acetylcholine, and glutamate drugs.

RATIONALE: Rodent vendors are often utilized interchangeably, assuming that the phenotype of a given strain remains standardized between colonies. Several studies, however, have found significant behavioral and physiological differences between Sprague Dawley (SD) rats from separate vendors. Prepulse inhibition of startle (PPI), a form of sensorimotor gating in which a low-intensity leading stimulus reduces the startle response to a subsequent stimulus, may also vary by vendor. Differences in PPI between rat strains are well known, but divergence between colonies within the SD strain lacks thorough examination. OBJECTIVES: We explored intrastrain variation in PPI by testing SD rats from two vendors: Envigo and Charles River (CR). METHODS: We selected drugs acting on four major neurotransmitter systems that have been repeatedly shown to modulate PPI: dopamine (apomorphine; 0.5, 1.5, 3.0 mg/kg), acetylcholine (scopolamine; 0.1, 0.5, 1.0 mg/kg), glutamate (dizocilpine; 0.5, 1.5, 2.5 mg/kg), and serotonin (2,5-Dimethoxy-4-iodoamphetamine, DOI; 0.25, 0.5, 1.0 mg/kg). We determined PPI and startle amplitude for each drug in male and female Envigo and CR SD rats. RESULTS: SD rats from Envigo showed dose-dependent decreases in PPI after apomorphine, scopolamine, or dizocilpine administration, without significant effects on startle amplitude. SD rats from CR were less sensitive to modulation of PPI and/or more sensitive to modulation of startle amplitude, across the three drugs. CONCLUSIONS: SD rats showed vendor differences in sensitivity to pharmacological modulation of PPI and startle. We encourage researchers to sample rats from separate vendors before experimentation to identify the most suited source of subjects for their specific endpoints.

Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour.

Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.

Prepulse inhibition deficit as a transdiagnostic process in neuropsychiatric disorders: a systematic review.

BACKGROUND: Psychopathological research is moving from a specific approach towards transdiagnosis through the analysis of processes that appear transversally to multiple pathologies. A phenomenon disrupted in several disorders is prepulse inhibition (PPI) of the startle response, in which startle to an intense sensory stimulus, or pulse, is reduced if a weak stimulus, or prepulse, is previously presented. OBJECTIVE AND METHODS: The present systematic review analyzed the role of PPI deficit as a possible transdiagnostic process for four main groups of neuropsychiatric disorders: (1) trauma-, stress-, and anxiety-related disorders (2) mood-related disorders, (3) neurocognitive disorders, and (4) other disorders such as obsessive-compulsive, tic-related, and substance use disorders. We used Web of Science, PubMed and PsycInfo databases to search for experimental case-control articles that were analyzed both qualitatively and based on their potential risk of bias. A total of 64 studies were included in this systematic review. Protocol was submitted prospectively to PROSPERO 04/30/2022 (CRD42022322031). RESULTS AND CONCLUSION: The results showed a general PPI deficit in the diagnostic groups mentioned, with associated deficits in the dopaminergic neurotransmission system, several areas implied such as the medial prefrontal cortex or the amygdala, and related variables such as cognitive deficits and anxiety symptoms. It can be concluded that the PPI deficit appears across most of the neuropsychiatric disorders examined, and it could be considered as a relevant measure in translational research for the early detection of such disorders.