Sensorimotor gating deficits in “two-hit” models of schizophrenia risk factors
Section snippets
Introduction: utility of prepulse inhibition in models relevant to schizophrenia
Sensorimotor gating occurs when a motor responses is gated by a sensory event. One form of sensorimotor gating that has been studied at multiple levels of biology, from its cellular mechanisms (Frost et al., 2003, Nusbaum and Contreras, 2004, Rose and Scott, 2003) to its relationship to neuropsychiatric disease (Braff, 2010, Braff, 2011, Swerdlow et al., 2008), is prepulse inhibition (PPI) of startle. PPI occurs when a weak, subthreshold stimulus presented 30–500 ms prior to an intense startling
Approaches to genetic discoveries
The two primary approaches to understanding the genetics of neuropsychiatric disease are the common disease/common allele approach (CDCA) and the common disease/rare allele approach (CDRA) (Arguello and Gogos, 2011). Candidate gene or unbiased genome-wide association studies (GWAS) focus on common genetic variants (> 5% allele frequency); whereas, the CDRA approach focuses on the hypothesis that rare variants with high penetrance can cause common disease (Arguello and Gogos, 2011). Schizophrenia
Neurodevelopmental risk factors
There is increasing evidence that schizophrenia has its roots in disrupted brain development due to both genetic and environmental risk factors, leading to psychosis emergence in adolescence and early adulthood (Cannon et al., 2003, Murray et al., 2002, Rapoport et al., 2012). Environmental risk factors are evident throughout development and include prenatal and perinatal risk factors, psychological risk factors in early life and adolescence, and exposure to drugs of abuse or trauma in
“Two hit” models of risk factors of schizophrenia
As reviewed above, early developmental factors are implicated in the pathogenesis of schizophrenia (Davis et al., 2016), and recent GWAS have identified multiple common schizophrenia risk alleles contributing small effect to disease risk (Owen et al., 2016). In addition to common variants with small effects, there is also evidence for the involvement of several large CNVs in schizophrenia (Ross et al., 2006). Additionally, there are several non-genetic second-hits (substance abuse (McKetin et
Discussion
Here we summarize schizophrenia risk factors, neurodevelopmental animal models, and the current findings from two hit models of these risk factors published in recent years. As reviewed above, we focused on PPI because of its strong relationship with schizophrenia, its heritability, and its sensitivity to developmental risk factors. Taken together, the studies suggest that some gene and environment combinations result in more pronounced PPI deficits than either manipulation alone. For example,
Conflict of interest statement
There are no financial/personal interests or beliefs that could affect the objectivity of the authors.
Contributors
Asma Khan and Susan Powell both wrote the manuscript.
Author agreement/declaration
I certify that all authors (Asma Khan and myself, Susan Powell) have seen and approved the final version of the manuscript being submitted. I warrant that this article is our (the authors') original work, hasn't received prior publication and isn't under consideration for publication elsewhere.
Funding source declaration
NIH grant ES025585 and Veteran's Affairs VISN 22 MIRECC supported the authors during the writing of this manuscript.
Acknowledgements
We thank Drs. Victoria Risbrough, Xianjin Zhou, and Tiffany Greenwood for helpful discussions and comments. This work was supported by ES025585 and by the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.
References (272)
- et al.
Social functioning in individuals at clinical high risk for psychosis
Schizophr. Res.
(2008) - et al.
Cannabis and schizophrenia a longitudinal study of Swedish conscripts
Lancet
(1987) - et al.
Animal models of gene-environment interaction in schizophrenia: a dimensional perspective
Prog. Neurobiol.
(2016) - et al.
Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family
Am. J. Hum. Genet.
(2001) Animal models of obstetric complications in relation to schizophrenia
Brain Res. Brain Res. Rev.
(2004)- et al.
Juvenile cannabinoid treatment induces frontostriatal gliogenesis in Lewis rats
Eur. Neuropsychopharmacol.
(2014) Gating in schizophrenia: from genes to cognition (to real world function?)
Biol. Psychiatry
(2011)- et al.
Prepulse inhibition and P50 suppression are both deficient but not correlated in schizophrenia patients
Biol. Psychiatry
(2007) - et al.
Maternal cytokine levels during pregnancy and adult psychosis
Brain Behav. Immun.
(2001) - et al.
Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring
Biol. Psychiatry
(2008)
Transient prenatal vitamin D deficiency is associated with hyperlocomotion in adult rats
Behav. Brain Res.
Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle
Physiol. Behav.
Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint
Behav. Brain Res.
Altered responses to novelty and drug reinforcement in adult rats treated neonatally with domoic acid
Physiol. Behav.
Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia
Neuron
Startle reactivity and prepulse inhibition in prodromal and early psychosis: effects of age, antipsychotics, tobacco and cannabis in a vulnerable population
Psychiatry Res.
Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction
Biol. Psychiatry
Developmental emergence of reelin deficits in the prefrontal cortex of Wistar rats reared in social isolation
Neuroscience
Reduced reelin protein synthesis in ventral hippocampus of isolation reared Wistar rats accompanies impaired avoidance conditioning
Behav. Brain Res.
Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results
Biol. Psychiatry
Maternal exposure to sexually transmitted infections and schizophrenia among offspring
Schizophr. Res.
Attenuated disruption of prepulse inhibition by dopaminergic stimulation after maternal deprivation and adolescent corticosterone treatment in rats
Eur. Neuropsychopharmacol.
The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains
Schizophr. Res.
A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis
Neurosci. Biobehav. Rev.
Age at onset of schizophrenia: cannabis, COMT gene, and their interactions
Schizophr. Res.
Combination of prenatal immune challenge and restraint stress affects prepulse inhibition and dopaminergic/GABAergic markers
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Preventive effect of alpha-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia
Neuroscience
Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users
Biol. Psychiatry
Cannabis use, gender and age of onset of schizophrenia: data from the AESOP study
Psychiatry Res.
Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity
Behav. Brain Res.
Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice
Neuroscience
The long-term effects of maternal deprivation depend on the genetic background
Neuropsychopharmacology
The effects of an early stressful life event on sensorimotor gating in adult rats
Schizophr. Res.
Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease
Front. Neuroendocrinol.
Developmental stress disrupts habituation but spares prepulse inhibition in young rats
Physiol. Behav.
A cellular mechanism for prepulse inhibition
Neuron
Association between cannabis and psychosis: epidemiologic evidence
Biol. Psychiatry
The teen brain: insights from neuroimaging
J. Adolesc. Health
Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders
Schizophr. Bull.
Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study
Schizophr. Bull.
Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder
Neuropsychopharmacology
Prepulse inhibition deficits in obsessive-compulsive disorder are more pronounced in females
Neuropsychopharmacology
Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences
Br. J. Psychiatry
Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes
Acta Psychiatr. Scand.
Cognition in mouse models of schizophrenia susceptibility genes
Schizophr. Bull.
Psychiatric genetics and the generation of mutant animal models
Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study
BMJ
Neonatal infection with neurotropic influenza a virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1-/- mice
Int. J. Neuropsychopharmacol.
Brain-derived neurotrophic factor and neuropsychiatric disorders
Pharmacol. Rev.
Comorbid substance use and age at onset of schizophrenia
Br. J. Psychiatry
Cited by (32)
Lack of interactions between prenatal immune activation and Δ<sup>9</sup>-tetrahydrocannabinol exposure during adolescence in behaviours relevant to symptom dimensions of schizophrenia in rats
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryThe 3-hit animal models of schizophrenia: Improving strategy to decipher and treat the disease?
2024, Neuroscience and Biobehavioral ReviewsUniversal automated classification of the acoustic startle reflex using machine learning
2023, Hearing ResearchCatechol-O-methyltransferase (COMT) Val158Met Polymorphism and Prepulse Inhibition of the Change-related Cerebral Response
2022, Psychiatry Research - NeuroimagingCitation Excerpt :In schizophrenia, a disturbance of this gating system might cause a flood of irrelevant sensory information and lead to the cognitive deficits that are often observed in individuals with schizophrenia. There have also been numerous PPI studies using animal models (Khan and Powell, 2018; Powell et al., 2012). Thus, the PPI of an ASR, as one of the well-established neurophysiological indexes, has been widely used in translational research in schizophrenia.
Systematic discovery of signaling pathways linking immune activation to schizophrenia
2021, iScienceCitation Excerpt :Rare variants are found to significantly increase the disease burden (Fromer et al., 2014; Singh et al., 2017; Xu et al., 2011), and they are suggested to have bigger effects and thus higher penetrance (Singh et al., 2017). Another challenge is that “gene-environment interaction” and “environment-environment interaction” may play a critical role in schizophrenia (Khan and Powell, 2018). The “Two-Hit Hypothesis” of schizophrenia, proposed in 1999, suggests that schizophrenia needs two events (“hits”) for its development: the first event (i.e., basic requirement) represents genetic factors such as germline mutations; and the second consists of environmental factors such as viral infections and social stressors (Bayer et al., 1999; Feigenson et al., 2014).