Dependency of prepulse inhibition deficits on baseline startle reactivity in a mouse model of the human 22q11.2 microdeletion syndrome

Abstract

Hemizygous microdeletion at the chromosomal locus 22q11.2 is a copy number variation with strong genetic linkage to schizophrenia and related disorders. This association, along with its phenotypic overlap with the 22q11.2 microdeletion syndrome, has motivated the establishment of Df[h22q11]/+ mice, in which the human 22q11.2 orthologous region is deleted. Previous investigations using this model showed the presence of reduced prepulse inhibition (PPI) of the acoustic startle reflex, a form of sensorimotor gating known to be impaired in a number of psychiatric disorders. Concomitantly to reduced PPI, however, Df[h22q11]/+ mice are also characterized by a robust increase in baseline startle reactivity, which may complicate or confound the interpretation of PPI. Therefore, the present study re-examined the relationship between acoustic startle reactivity and PPI in this mouse model. We found that while PPI is reduced in Df [h22q11]/+ mice when using its relative indexation (ie, % PPI), this deficit is no longer apparent when using the absolute quantification, that is, the direct comparison between pulse-alone and prepulse-plus-pulse conditions with successively increasing prepulse intensities. We further identified marked negative correlations between % PPI and startle reactivity in Df[h22q11]/+ mice. Moreover, when stratifying Df[h22q11]/+ mice into subgroups displaying low-and highstartle reactivity, only the latter subgroup displayed a significant reduction in % PPI. Collectively, our data suggest that alterations in baseline startle reactivity can confound the outcomes and interpretation of PPI in this mouse model of the human 22q11.2 microdeletion syndrome. K E Y W O R D S 22q11.2 microdeletion, autism, copy number variation (CNV), prepulse inhibition, schizophrenia, sensorimotor gating, startle reactivity 1 | INTRODUCTION Gene copy number variation (CNVs) are genetic variations that are characterized by deletions or duplications of specific DNA sequences. 1,2 Hemizygous microdeletion at chromosomal locus 22q11.2 is one of the most common CNVs, with an estimated prevalence of over 1 in 4000 live births. 3 It is associated with increased incidence rates of cognitive impairment and neuropsychiatric disorders, including obsessive-compulsive disorder, 4 attention deficit hyperactivity disorder, 5,6 autism spectrum disorder 6 and schizophrenia. 7 Hemizygous 22q11.2 microdeletion is currently the strongest known genetic risk factor of schizophrenia, with 20-40% of carriers developing psychosis-related dysfunctions. 8 Approximately 90% of 22q11.2 deletions are~3 Mb, whereas the remainder includes a nested~1.5 or~2 Mb deletion or some atypical, non-nested distal deletions. 9 As extensively reviewed elsewhere, 9 the deletion affects a number of neighboring genes, most of which are conserved on mouse chromosome 16. 10 The preservation of genes has motivated the establishment of mouse models, in which the human 22q11.2 orthologous genomic region is deleted on mouse

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

“…Interestingly, fluctuations of psychotic symptoms in SZ resemble the relapsing remitting pattern of prototypical immunological disorders, suggesting that the peripheral inflammation 5 22qDS+SZ iBBB exhibited substantially impaired barrier integrity, despite the genetic variability introduced by our approach. This phenotype was substantiated in vivo in a 22qDS mouse model harboring a homologous hemizygous deletion (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). We further interrogated junctional protein expression and immune privilege properties of the BBB in vitro and in vivo.…”

“…To evaluate the 22qDS BBB in vivo, we utilized a mouse strain harboring a hemizygous deletion of the 22qDS homologous region on chromosome 16 (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). These mice mimic much of the biology of 22qDS in humans, including facial deformities and SZ-associated behavioral changes (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). We assessed BBB integrity by quantifying extravasation of blood proteins into the CNS parenchyma of 22qDS mice and their wild type (WT) littermates.…”

Sex- and age-dependent contribution of System xc– to cognitive, sensory, and social behaviors revealed by comprehensive behavioral analyses of System xc– null mice

“…Sensorimotor gating is a critical process for preventing sensory overload to ensure normal information processing ( Ioannidou et al, 2018 ; Gómez-Nieto et al, 2020 ). Since baseline startle response can be a confounding factor in interpreting PPI ( Yee et al, 2005 ; Shoji and Miyakawa, 2018 ; Scarborough et al, 2019 ), we analyzed both PPI and the ASR individually. Interestingly, we observed intact PPI in all mice regardless of sex and genotype, indicating their ability to suppress a motor response after a prepulse preceded the startle stimulus ( Figure 9 ).…”

Ileal Dysbiosis Is Associated with Increased Acoustic Startle in the 22q11.2 Microdeletion Mouse Model of Schizophrenia

“…We observed increased acoustic startle response in the Q22 model, but in contrast to previously published studies we did not observe reduced % prepulse inhibition in Q22 mice [ 15 , 17 ]. This may have been confounded by the robust increased startle response at baseline or “first startle”—meaning prior to any prepulse + pulse trial—requiring a larger sample size to elucidate the effect on % prepulse inhibition [ 40 ]. In general, small sample sizes, particularly for the open-field and object-in-place tasks, were a limitation in this study.…”