Deficient Prepulse Inhibition Research Articles

Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment

We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP−/−) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder) show abnormalities in the axon initial segment (AIS). Here, we revealed that PACAP−/− mice exhibited a longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field compared with wild-type control mice. Further, we previously showed that a single injection of atomoxetine, an ADHD drug, improved hyperactivity in PACAP−/− mice. In this study, we found that repeated treatments of atomoxetine significantly improved AIS abnormality along with hyperactivity in PACAP−/− mice. These results suggest that AIS abnormalities are associated with NDDs-like behaviors in PACAP−/− mice. Thus, improvement in AIS abnormalities will be a novel drug therapy for NDDs.

Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology.

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.

Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice

SummaryFrom genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with schizophrenia.

Deep brain stimulation and sensorimotor gating in tourette syndrome and obsessive-compulsive disorder

Recent translational data suggest that deep brain stimulation (DBS) of the cortico-striato-thalamo-cortical (CSTC) loops improves sensorimotor gating in psychiatric disorders that show deficient prepulse inhibition (PPI), a robust operational measure of sensorimotor gating. To our knowledge we are the first to investigate this effect in patients with Tourette syndrome (TS). We measured PPI of the acoustic startle reflex in patients with TS (N = 10) or Obsessive-Compulsive Disorder (OCD) (N = 8) treated with DBS of the centromedian and ventro-oral internal thalamic nucleus and the anterior limb of internal capsule–nucleus accumbens area respectively, and aged- and gender-matched healthy controls (HC). PPI of the DBS groups was measured in randomized order in the ON and OFF stimulation condition. Statistical analysis revealed no significant difference in PPI (%) of patients with TS between ON (M = 20.5, SD = 14.9) and OFF (M = 25.2, SD = 29.7) condition. There were significantly reduced PPI levels in patients with TS in the ON condition compared to HC (M = 49.2, SD = 10.7), but no significant difference in PPI between TS in the OFF condition and HC. Furthermore, we found no significant stimulation or group effect for OCD and HC (OCD ON: M = 57.0, SD = 8.3; OCD OFF: 67.8, SD = 19.6; HC: M = 63.0, SD = 24.3). Our study has a number of limitations. Sample sizes are small due to the restricted patient collective. The study was not controlled for use of psychoactive medication or nicotine. Furthermore, we were not able to assess presurgical PPI measurements. In conclusion, we were able to show that PPI is impaired in patients with TS. This finding is in line with recent translational work. With respect to the OCD cohort we were not able to replicate our previously published data. A disability in sensorimotor gating plays a pivotal role in many psychiatric disorders therefore more research should be conducted to disentangle the potential and limitations of modulating sensorimotor gating via brain stimulation techniques.

Strategic Timing of Glial HMOX1 Expression Results in Either Schizophrenia-Like or Parkinsonian Behavior in Mice.

Aims: In this original research communication, we assess the impact of shifting the window of glial HMOX1 overexpression in mice from early-to-midlife to mid-to-late life, resulting in two disparate conditions modeling schizophrenia (SCZ) and Parkinson's disease (PD). Mesolimbic hyperdopaminergia is a widely accepted feature of SCZ, while nigrostriatal hypodopaminergia is the sine qua non of idiopathic PD. Although the advent of parkinsonian features in SCZ patients after treatment with antidopaminergic agents is intuitive, subtle features of parkinsonism commonly observed in young, drug-naïve schizophrenics are not. Similarly, emergent psychosis in PD subjects receiving levodopa replacement is not unusual, whereas spontaneous hallucinosis in nonmedicated persons with idiopathic PD is enigmatic. Investigations using GFAP.HMOX1 mice may shed light on these clinical paradoxes. Results: Astroglial heme oxygenase-1 (HO-1) overexpression in mice throughout embryogenesis until 6 or 12 months of age resulted in hyperdopaminergia, hyperkinesia/stereotypy ameliorated with clozapine, deficient prepulse inhibition of the acoustic startle response, reduced preference for social novelty, impaired nest building, and cognitive dysfunction reminiscent of SCZ. On the contrary, astroglial HO-1 overexpression between 8.5 and 19 months of age yielded a PD-like behavioral phenotype with hypodopaminergia, altered gait, locomotor incoordination, and reduced olfaction. Innovation: We conjecture that region-specific disparities in the susceptibility of dopaminergic and other circuitry to the trophic and degenerative influences of glial HMOX1 induction may permit the concomitant expression of mixed SCZ and PD traits within affected individuals. Conclusion: Elucidation of these converging mechanisms may (i) help better understand disease pathogenesis and (ii) identify HO-1 as a potential therapeutic target in neurodevelopmental and neurodegenerative disorders.

NMDA receptors on parvalbumin-positive interneurons and pyramidal neurons both contribute to MK-801 induced gamma oscillatory disturbances: Complex relationships with behaviour

BackgroundNMDAr antagonists induce disturbances to gamma frequency oscillations, including increasing ongoing gamma activity and reducing evoked gamma oscillations. We sought to investigate the role parvalbumin (PV+) neurons and CaMKIIα+ pyramidal cells in NMDAr antagonist-induced disturbances in gamma oscillatory activity and relate these to common behavioural consequences of these drugs by selectively deleting the obligatory GluN1 subunit from these cells in mice. MethodsAdult mice (total n = 99) with GluN1 deleted from PV interneurons (PV:GluN1 KO) or CaMKIIα+ pyramidal cells (CaMKIIα:GluN1 KO), and WT littermates, were used. We assessed effects of the NMDAr antagonist MK-801 on prepulse inhibition (PPI) and locomotor behaviour. Then, mice were implanted with electrodes in the prefrontal cortex (mPFC) and hippocampus (dHPC), and the effects of MK-801 on gamma oscillations assessed. ResultsIn WT mice, MK-801 increased ongoing gamma power, reduced evoked gamma power and increased gamma coherence. These changes were accompanied by hyperlocomotion and deficient PPI. The consequences of NMDAr antagonism were differentially regulated in the transgenic mice. The MK-801-induced increase in ongoing gamma power was significantly attenuated in both transgenic strains, but deficits to evoked gamma activity were unaffected by genotype. Deficient PPI was not affected by genotype, and only in PV:GluN1 KO mice was the hyperlocomotor phenotype of MK-801 attenuated. The emergence of abnormal gamma band hyperconnectivity between the mPFC and dHPC was absent in CaMKIIα:GluN1 KO mice. ConclusionThis study suggests that the effects of NMDAr antagonism on gamma band responses and behaviour have complex relationships, and rely on different populations of neurons.

Deep brain stimulation of the thalamic centromedian-parafascicular nucleus improves behavioural and neuronal traits in a rat model of Tourette

Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats.Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150 μA and 130 Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0 mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS.CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS.Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.

Increased exploratory activity in rats with deficient sensorimotor gating: a study of schizophrenia-relevant symptoms with genetically heterogeneous NIH-HS and Roman rat strains

Schizophrenia involves positive, negative and cognitive symptoms, as well as comorbidity with anxiety and obsessive-compulsive disorder. Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in schizophrenia and animal models of the disease. Remarkably, impaired PPI has been related to other schizophrenia-like features in rodent models, such as cognitive deficits and hyperactivity. However, it remains to be investigated whether deficient PPI and increased exploratory activity are associated in genetically heterogeneous (outbred) naïve animals. This study was undertaken to evaluate the relationships among PPI and other schizophrenia-related symptoms, such as augmented exploratory activity, anxiety and compulsivity in the genetically heterogeneous (outbred) NIH-HS rat stock (HS) and in the genetically-selected inbred Roman High-Avoidance (RHA) and Low-avoidance (RLA) rats. Animals underwent the following tests: open-field (exploratory activity), elevated zero-maze (anxiety-like behavior), marble burying (compulsive-like behavior), and PPI. Three groups of HS rats were formed according to their PPI scores, i.e. Low-PPI, Medium-PPI and High-PPI. The HS Low-PPI group displayed higher exploratory activity in the open-field than the HS Medium-PPI and HS High-PPI groups. Likewise, compared with their RLA counterparts, RHA rats exhibited lower PPI and more intense exploratory activity in the open-field test. Correlational and factorial analyses of the whole HS sample and the RHA/RLA data globally corroborated the results of the PPI-stratified HS subgroups. These data suggest that such a consistent association between impaired PPI and increased exploratory activity in outbred HS and inbred RHA/RLA rats is a relevant parameter that must be taken into account when modeling clusters of schizophrenia-relevant symptoms.

The MAM-E17 schizophrenia rat model: Comprehensive behavioral analysis of pre-pubertal, pubertal and adult rats.

The MAM-E17 model is one of the most accepted schizophrenia rat models, which follows the neurodevelopmental theory of the disease. While symptoms of MAM-E17 rats were studied extensively, their examinations were usually restricted to adulthood and in a few cases to prepuberty. It is well known, however, that schizophrenia symptoms often start at puberty or early adulthood. Therefore the purpose of this study was to investigate the behavioral characteristics of MAM-E17 rats in various tests throughout three different age-periods, namely in prepuberty, late puberty and adulthood. In open field test, MAM-E17 rats displayed increased locomotor activity, elevated sniffing frequency and, as tendency, enhanced rearing activity. The elevated activity turned up in late puberty and remained there in adulthood, too. There was also a deficient prepulse inhibition (PPI) of startle response in late puberty and adulthood, but not before puberty. In rotarod task, MAM-treated rats performed better than control rats. The enhanced performance on rotarod was only present in late puberty and adulthood. In elevated plus maze test MAM-treated rats displayed diminished anxiety mostly in prepuberty. Histological analysis revealed reduced volume and cell disarray in the dorsal hippocampus. This is the first comprehensive study about symptoms of MAM-E17 rats manifested in behavioral tests carried out in prepuberty, late puberty and adulthood. Results display the age-dependent appearance of schizophrenia symptoms in the same rats. The present findings provide basic information to accomplish the schizophrenia related animal research, as well as can also confer further data to develop preventive treatment for human patients.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension

BackgroundThe Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first “wave” (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS “wave” (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. MethodsPPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, “wave” (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. ResultsANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across “waves” (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of “wave” or “wave x diagnosis” interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DiscussionSchizophrenia-linked PPI deficits were replicable across two multi-site “waves” of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Deficient prepulse inhibition of blink reflex in migraine and its relation to allodynia

Prepulse inhibition (PPI) of the blink reflex (BR) is a reduction in BR excitability due to a conditioning stimulus, reflecting sensory gating by brainstem structures. We aimed to analyze PPI changes during a painful episode in chronic or episodic migraine and its relation to allodynia, since abnormal brainstem filtering has been hypothesized in migraine pathophysiology. We included 20 patients with migraine during headache episode, and age- and gender-matched 22 healthy subjects. We recorded BR after unconditioned and conditioned supraorbital stimuli. For conditioned stimuli, we applied preceding subthreshold stimulus to the median nerve at wrist. The presence of PPI was compared between the two groups, as well as the specific BR parameters (latency, amplitude or area of R1 and R2 components) in unconditioned (test) and conditioned (PPI) paradigms. In the patient group, seven (35%) patients did not have R2-PPI whereas all healthy subjects had R2-PPI (P=0.003). Healthy subjects displayed significantly increased R1 amplitude and reduced R2 amplitude and area after conditioned stimuli. In migraine patients, we observed significant reduction only in R2 amplitude. Logistic regression demonstrated that allodynia was independently related with the presence of PPI (beta: -0.535, P=0.021). Our study provides evidence for sensory gating impairment at brainstem level in migraine headache, related to the presence of allodynia.

Prepulse inhibition in euthymic bipolar disorder patients in comparison with control subjects.

Deficient prepulse inhibition (PPI) of the startle response, indicating sensorimotor gating deficits, has been reported in schizophrenia and other neuropsychiatric disorders. This study aimed to assess sensorimotor gating deficits in patients with euthymic bipolar. Furthermore, we analysed the relationships between PPI and clinical and cognitive measures. Prepulse inhibition was measured in 64 patients with euthymic bipolar and in 64 control subjects matched for age, gender, education level and smoking status. Clinical characteristics and level of functioning were assessed in all participants using Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS) and Functioning Assessment Short Test (FAST). Cognition was evaluated using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) and the Stroop test as an additional measure of executive function. Compared with controls, patients with bipolar disorder exhibited PPI deficits at 60- and 120-millisecond prepulse-pulse intervals. Among patients with bipolar disorder, PPI was correlated with the social cognition domain of the MCCB. PPI was not significantly correlated with other clinical, functional and neurocognitive variables in either group. Our data suggest that PPI deficit is a neurobiological marker in euthymic bipolar disorder, which is associated with social cognition but not with other clinical, functional or cognitive measures.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis.

Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice.

Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation.

Neuronal activity of the prefrontal cortex is reduced in rats selectively bred for deficient sensorimotor gating.

Rats selectively bred for deficient prepulse inhibition (PPI), an operant measure of sensorimotor gating in which a weak prepulse stimulus attenuates the response to a subsequent startling stimulus, may be used to study certain pathophysiological mechanisms and therapeutic strategies for neuropsychiatric disorders with abnormalities in information processing, such as schizophrenia and Tourette's syndrome (TS). Little is known about neuronal activity in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), which are involved in the modulation of PPI. Here, we examined neuronal activity in these structures, and also in the entopeduncular nucleus (EPN), since lesions of this region alleviate the PPI deficit. Male rats with breeding-induced high and low expression of PPI (n=7, each) were anesthetized with urethane (1.4 mg/kg). Single-unit activity and local field potentials were recorded in the mPFC, the NAC and in the EPN. In the mPFC discharge rate, measures of irregularity and burst activity were significantly reduced in PPI low compared to PPI high rats (P<0.05), while analysis in the NAC showed approximately inverse behavior. In the EPN no difference between groups was found. Additionally, the oscillatory theta band activity (4-8 Hz) was enhanced and the beta band (13-30 Hz) and gamma band (30-100 Hz) activity was reduced in the NAC in PPI low rats. Reduced neuronal activity in the mPFC and enhanced activity in the NAC of PPI low rats, together with altered oscillatory behavior are clearly associated with reduced PPI. PPI low rats may thus be used to study the pathophysiology and therapeutic strategies for neuropsychiatric disorders accompanied by deficient sensorimotor gating.

Clonidine Normalizes Sensorimotor Gating Deficits in Patients With Schizophrenia on Stable Medication

Cognitive deficits form core features in schizophrenia. Several studies have shown improvements in prefrontal cognitive function by α 2 -agonists in schizophrenia. In the present study, it was investigated whether clonidine (an α 2 -adrenoceptor agonist) could normalize sensorimotor gating deficits in schizophrenia. In a double blind, placebo controlled, randomized, yet balanced, cross-over experiment, 20 male schizophrenia patients on stable medication were assessed in an auditory prepulse inhibition (PPI), sensitization, and habituation of the startle reflex paradigm on 5 occasions: once after oral administration of placebo and after a single dose of 25, 50, 75, and 150 µg of clonidine. Their results were compared with 20 age- and gender-matched healthy volunteers, who received no treatment. In the placebo treatment, patients showed deficient PPI and sensitization, yet normal habituation compared with the controls. Except the highest dose, all dosages of clonidine significantly increased percentage PPI in the patients compared with placebo, to such levels that it no longer differed significantly from the healthy controls. However, none of the dosages increased sensitization or influenced habituation. This is the first study to show that even a single low dose of clonidine added to the medical treatment of patients with schizophrenia who are clinically stable on their antipsychotic medication not only significantly ameliorates their PPI deficits, but also normalizes them. The results have a potentially high clinical relevance for the medical treatment of schizophrenia.

Narcolepsy–cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement

Hypocretin (orexin) deficiency plays a major role in the pathophysiology of narcolepsy-cataplexy. In animal models, hypocretinergic projections to the pedunculopontine nucleus are directly involved in muscle tone regulation mediating muscle atonia - a hallmark of cataplexy. We hypothesized that pedunculopontine nucleus function, tested with prepulse inhibition of the blink reflex, is altered in human narcolepsy-cataplexy. Twenty patients with narcolepsy-cataplexy and 20 healthy controls underwent a neurophysiological study of pedunculopontine nucleus function. Blink reflex, prepulse inhibition of the blink reflex and blink reflex excitability recovery were measured. Blink reflex characteristics (R1 latency and amplitude, and R2 and R2c latency and area under the curve) did not differ between patients and controls (P > 0.05). Prepulse stimulation significantly increased R2 and R2c latencies and reduced R2 and R2c areas in patients and controls. However, the R2 and R2c area suppression was significantly less in patients than in controls (to 69.8 ± 14.4 and 74.9 ± 12.6%, respectively, versus 34.5 ± 28.6 and 43.3 ± 29.5%, respectively; each P < 0.001). Blink reflex excitability recovery, as measured by paired-pulse stimulation, which is not mediated via the pedunculopontine nucleus, did not differ between patients and controls (P > 0.05). Our data showed that prepulse inhibition is reduced in narcolepsy-cataplexy, whereas unconditioned blink reflex and its excitability recovery are normal. Because the pedunculopontine nucleus is important for prepulse inhibition, these results suggest its functional involvement in narcolepsy-cataplexy.

Deep brain stimulation of the entopeduncular nucleus in rats prevents apomorphine-induced deficient sensorimotor gating

Pharmacologically induced stereotypies and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as endophenotypes for certain symptoms common to neuropsychiatric disorders, such as schizophrenia and Tourette's syndrome (TS) among others. We here investigated whether high frequency deep brain stimulation (DBS) of the rat's entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve PPI-deficits and stereotypies induced by the dopamine receptor agonist apomorphine.Electrodes were stereotactically implanted bilaterally in the EPN of 13 Sprague-Dawley rats. After one week of recovery the rats were stimulated with an amplitude 20% below their individual threshold for side effects (130Hz, 80μs pulse width) or sham-stimulated for epochs of five days. At the end of each epoch the effect of ongoing stimulation or sham-stimulation on apomorphine-induced stereotypies (vehicle and 0.5mg/kg) and deficient PPI (vehicle and 1.0mg/kg) were tested.In nine rats, in which the full protocol could be applied and in which the electrode position was histologically confirmed in the target, EPN DBS did not affect baseline PPI but counteracted the apomorphine-induced PPI-deficit, while apomorphine-induced stereotypies were not affected by DBS.This work indicates an important role of the EPN in the modulation of apomorphine-induced deficient prepulse inhibition. This model may be useful to further investigate the pathophysiological of deficient sensorimotor gating and mechanisms of action of DBS in certain neuropsychiatric disorders.

Deep brain stimulation of the subthalamic nucleus in the 6-hydroxydopamine rat model of Parkinson's disease: Effects on sensorimotor gating

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effectively used to treat motor symptoms in Parkinson's disease (PD). Recently more attention has been paid to behavioral disturbances caused by PD itself and by STN DBS. In the 6-hydroxydopamine (6-OHDA) PD rat model we investigated the effect of STN DBS on deficient prepulse inhibition (PPI) induced by the dopamine (DA) receptor agonist apomorphine, which is an operative measure for disturbed sensorimotor gating seen in certain neuropsychiatric disturbances.Male Sprague Dawley rats with bilateral lesions of the nigrostriatal DA system (striatal injection of 6-OHDA or vehicle for sham-lesion) were bilaterally implanted with electrodes for DBS into the STN. After determination of individual thresholds rats were stimulated (130Hz, 80μs pulse width) or sham-stimulated for epochs of six days. On the sixth day of each epoch rats were tested for PPI of the acoustic startle response after apomorphine or vehicle injection in a within randomized cross-over design.Stimulation of the STN improved PPI in vehicle-treated (control) rats, but deteriorated PPI after apomorphine treatment. This effect was more pronounced in sham-lesioned rats. Furthermore, in lesioned rats the startle reaction was marginally enhanced without effect of stimulation or apomorphine treatment.These data suggest that STN DBS interacts with dopaminergic action. With respect to functional neurosurgery, STN DBS alone may improve certain aspects of psychiatric disturbances, but may have a different impact when combined with dopaminergic medication.