Early Schizophrenia and Bipolar Disorder Patients Display Reduced Neural Prepulse Inhibition

Background: Altered sensorimotor gating has been demonstrated by Prepulse Inhibition (PPI) tests in patients with psychosis. Recent advances in signal processing methods allow assessment of neural PPI through electroencephalogram (EEG) recording during acoustic startle response measures (classic muscular PPI). Simultaneous measurements of muscular (eye-blink) and neural gating phenomena during PPI test may help to better understand sensorial processing dysfunctions in psychosis. In this study, we aimed to assess simultaneously muscular and neural PPI in early bipolar disorder and schizophrenia patients. Method: Participants were recruited from a population-based case-control study of first episode psychosis. PPI was measured using electromyography (EMG) and EEG in pulse alone and prepulse + pulse with intervals of 30, 60, and 120 ms in early bipolar disorder (n = 18) and schizophrenia (n = 11) patients. As control group, 15 socio-economically matched healthy subjects were recruited. All subjects were evaluated with Rating Scale, Hamilton Rating Scale for Depression, and Young Mania Rating Scale questionnaires at recruitment and just before PPI test. Wilcoxon ranked sum tests were used to compare PPI test results between groups. Results: In comparison to healthy participants, neural PPI was significantly reduced in PPI 30 and PPI60 among bipolar and schizophrenia patients, while muscular PPI was reduced in PPI60 and PPI120 intervals only among patients with schizophrenia. Conclusion: The combination of muscular and neural PPI evaluations suggested distinct impairment patterns among schizophrenia and bipolar disorder patients. Simultaneous recording may contribute with novel information in sensory gating investigations.

Behavioural consequences of Setd1a haploinsufficiency in mice: evidence for heightened emotional reactivity and impaired sensorimotor gating

ABSTRACTA number of studies implicate the loss of function (LoF) mutations affecting the histone methyl transferase SETD1A in the aetiology of a range of neurodevelopmental disorders including schizophrenia. Here, we examined the behavioural consequences of haploinsufficiency of Setd1a in a mouse model. We find evidence for changes in a number of phenotypes of relevance to schizophrenia, including increased anxiety-related behaviour, enhanced acoustic startle response, and decreased pre-pulse inhibition of acoustic startle. The sensorimotor gating deficits in Setd1a+/- mice could not be rescued by haloperidol or risperidone, suggesting that these antipsychotics are ineffective for ameliorating schizophrenia-relevant phenotypes in Setd1a+/- mice and point to deficits in neural systems other than the monoamine system. These phenotypes are emerging as key features of a number of other mouse models of rare neurodevelopmental disorders caused by LoF mutations in genes encoding epigenome modifiers suggesting they may act in a network to modulate brain development. Taken together these data strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia, and point towards possible underpinning neural mechanisms.

cacna2d3, a voltage-gated calcium channel subunit, functions in vertebrate habituation learning and the startle sensitivity threshold

The ability to filter sensory information into relevant versus irrelevant stimuli is a fundamental, conserved property of the central nervous system and is accomplished in part through habituation learning. Synaptic plasticity that underlies habituation learning has been described at the cellular level, yet the genetic regulators of this plasticity remain poorly understood, as do circuits that mediate sensory filtering. A forward genetic screen for zebrafish genes that control habituation learning identified a mutant allele doryp177 that caused reduced habituation of the acoustic startle response. Whole-genome sequencing identified the calcium voltage-gated channel auxiliary subunit alpha-2/delta-3 (cacna2d3) as a candidate gene affected in doryp177 mutants. Behavioral characterization of larvae homozygous for two additional, independently derived mutant alleles of cacna2d3, together with failure of these alleles to complement doryp177, confirmed a critical role for cacna2d3 in habituation learning. Notably, detailed analyses of the acoustic response in mutant larvae also revealed increased startle sensitivity to acoustic stimuli, suggesting a broader role for cacna2d3 in controlling innate response thresholds to acoustic stimuli. Taken together, our data demonstrate a critical role for cacna2d3 in sensory filtering, a process that is disrupted in human CNS disorders, e.g. ADHD, schizophrenia, and autism.

Looming Effects on Attentional Modulation of Prepulse Inhibition Paradigm

In a hazardous environment, it is fundamentally important to successfully evaluate the motion of sounds. Previous studies demonstrated “auditory looming bias” in both macaques and humans, as looming sounds that increased in intensity were processed preferentially by the brain. In this study on rats, we used a prepulse inhibition (PPI) of the acoustic startle response paradigm to investigate whether auditory looming sound with intrinsic warning value could draw attention of the animals and dampen the startle reflex caused by the startling noise. We showed looming sound with a duration of 120 ms enhanced PPI compared with receding sound with the same duration; however, when both sound types were at shorter duration/higher change rate (i.e., 30 ms) or longer duration/lower rate (i.e., more than 160 ms), there was no PPI difference. This indicates that looming sound–induced PPI enhancement was duration dependent. We further showed that isolation rearing impaired the abilities of animals to differentiate looming and receding prepulse stimuli, although it did not abolish their discrimination between looming and stationary prepulse stimuli. This suggests that isolation rearing compromised their assessment of potential threats from approaching objects and receding objects.

Body Spasms in a Woman With Thyroid Disease

A 46-year-old woman with a history of autoimmune Hashimoto thyroiditis sought care for a 6-month history of spasms affecting her back and bilateral proximal lower extremities. On examination, the patient appeared anxious, and her whole body seemed to stiffen when the examiner entered the room. Her cognitive, cranial nerve, and upper extremity examinations were normal, except for brisk deep tendon reflexes. Examination of the patient’s spine indicated hyperlordosis of the lumbar region. There was visible hypertrophy of the lumbar paraspinal muscles. When asked to walk, the patient took short, tentative steps, despite having normal strength in her lower extremities. Her lower extremity tone demonstrated diffuse rigidity. Cerebrospinal fluid evaluation showed isolated increased protein concentration. Autoantibody testing of the serum and cerebrospinal fluid showed markedly increased levels of glutamic acid decarboxylase 65-kDa isoform–immunoglobulin G antibody in serum and in cerebrospinal fluid. Neurophysiologic studies in a movement disorders laboratory indicated a nonhabituating, exaggerated, acoustic startle response. Stiff-person syndrome was diagnosed. The patient received diazepam for symptomatic relief. At her follow-up visit, the patient reported reduction in frequency and severity of spasms but persistent stiffness throughout the lower back and lower extremities. Intravenous immunoglobulin was. After 3 months, the patient reported a 50% further improvement in stiffness and spasms but still required a walking aid. Physical therapy sessions focused on gait and safety, the patient was able to resume ambulation with a cane, without further falls. Stiff-person syndrome was described by Moersch and Woltman at Mayo Clinic in 1956. It most commonly arises in women of middle age but can affect men, women, and children. It is an autoimmune disorder of brainstem and spinal cord inhibitory interneuronal pathways, leading to what is termed central hyperexcitability.

Map2k5-Deficient Mice Manifest Phenotypes and Pathological Changes of Dopamine Deficiency in the Central Nervous System

MAP2K5, a member of the MAPK family, is associated with central nervous system disorders. However, neural functional of Map2k5 from animal models were not well examined so far. Here, we established a Map2k5-targeted knockout mouse model to investigate the behavior phenotypes and its underlying molecular mechanism. Our results showed that female Map2k5 mutant mice manifested decreased circadian-dependent ambulatory locomotion, coordination, and fatigue. Male Map2k5 mutant mice displayed impairment in open field exploration and prepulse inhibition of acoustic startle response (ASR) when compared with wild-type controls. Furthermore, Map2k5 mutant mice showed a decreased dopaminergic cell survival and tyrosine hydroxylase levels in nigrostriatal pathway, indicating a crucial role of MAP2K5 in regulating dopamine system in the central nervous system. In conclusion, this is the first study demonstrating that Map2k5 mutant mice displayed phenotypes by disturbing the dopamine system in the central nervous system, implicating Map2k5 mutant mouse as a promising model for many dopamine related disorders.

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

The acoustic startle response is an evolutionarily conserved avoidance behavior. Disruptions in startle behavior, particularly startle magnitude, are a hallmark of several human neurological disorders. While the neural circuitry underlying startle behavior has been studied extensively, the repertoire of genes and genetic pathways that regulate this locomotor behavior has not been explored using an unbiased genetic approach. To identify such genes, we took advantage of the stereotypic startle behavior in zebrafish larvae and performed a forward genetic screen coupled with whole genome analysis. We uncovered mutations in eight genes critical for startle behavior, including two genes encoding proteins associated with human neurological disorders, Dolichol kinase (Dolk), a broadly expressed regulator of the glycoprotein biosynthesis pathway, and the potassium Shaker-like channel subunit Kv1.1. We demonstrate that Kv1.1 and Dolk play critical roles in the spinal cord to regulate movement magnitude during the startle response and spontaneous swim movements. Moreover, we show that Kv1.1 protein is mislocalized in dolk mutants, suggesting they act in a common genetic pathway. Combined, our results identify a diverse set of eight genes, all associated with human disorders, that regulate zebrafish startle behavior and reveal a previously unappreciated role for Dolk and Kv1.1 in regulating movement magnitude via a common genetic pathway.

The effects of predator odor (TMT) exposure and mGlu3 NAM pretreatment on lasting behavioral and molecular adaptations in the insular cortex and BNST

A stressor can trigger adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that produces lasting adaptations. TMT exposure may activate metabotropic glutamate receptor 3 (mGlu3), triggering excitatory corticolimbic adaptations that underlie behavioral changes. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after stressor, rats underwent behavioral testing (context re-exposure, zero maze and acoustic startle response) followed by RT-PCR gene expression in the insular cortex and BNST. During the TMT exposure, rats displayed stress-reactive behaviors that were not affected by the VU6010572. During the context re-exposure, prior TMT exposure and VU6010572 pretreatment both produced a hyperactive response. TMT exposure did not affect zero maze or ASR measures, but VU6010572 increased time spent in the open arms and habituation to ASR, indicating anxiolytic-like effects. In the insular cortex, TMT exposure resulted in excitatory adaptations as shown by increased expression of mGlu (Grm3, Grm5), NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) and AMPA (GriA3) receptor transcripts. Interestingly, mGlu3 signaling during stressor mediated GriN3B upregulation. Stress reactivity during TMT exposure was associated with Grm5, GriN2A, GriN2C, and GriA3 upregulation in the insular cortex and context re-exposure reactivity in the TMT/vehicle, but not the TMT/mGlu3 NAM group. In the BNST, GriN2A, GriN2B and GriN3B were increased by VU6010572, but TMT prevented these effects. These data demonstrate that mGlu3 signaling contributes to the lasting behavioral and molecular adaptations of predator odor stressor.

Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

Acoustically Enriched Environment during the Critical Period of Postnatal Development Positively Modulates Gap Detection and Frequency Discrimination Abilities in Adult Rats

Throughout life, sensory systems adapt to the sensory environment to provide optimal responses to relevant tasks. In the case of a developing system, sensory inputs induce changes that are permanent and detectable up to adulthood. Previously, we have shown that rearing rat pups in a complex acoustic environment (spectrally and temporally modulated sound) from postnatal day 14 (P14) to P28 permanently improves the response characteristics of neurons in the inferior colliculus and auditory cortex, influencing tonotopical arrangement, response thresholds and strength, and frequency selectivity, along with stochasticity and the reproducibility of neuronal spiking patterns. In this study, we used a set of behavioral tests based on a recording of the acoustic startle response (ASR) and its prepulse inhibition (PPI), with the aim to extend the evidence of the persistent beneficial effects of the developmental acoustical enrichment. The enriched animals were generally not more sensitive to startling sounds, and also, their PPI of ASR, induced by noise or pure tone pulses, was comparable to the controls. They did, however, exhibit a more pronounced PPI when the prepulse stimulus was represented either by a change in the frequency of a background tone or by a silent gap in background noise. The differences in the PPI of ASR between the enriched and control animals were significant at lower (55 dB SPL), but not at higher (65-75 dB SPL), intensities of background sound. Thus, rearing pups in the acoustically enriched environment led to an improvement of the frequency resolution and gap detection ability under more difficult testing conditions, i.e., with a worsened stimulus clarity. We confirmed, using behavioral tests, that an acoustically enriched environment during the critical period of development influences the frequency and temporal processing in the auditory system, and these changes persist until adulthood.