Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Abstract

IntroductionThe 22q11.2 hemizygous microdeletion confers very high risk for neurodevelopmental disorders, including autism and schizophrenia (22q11.2 deletion syndrome [22q11.2DS]). The estimated prevalence is approximately 1 in 2000.1 The International Consortium on Brain and Behaviour in 22q11.2 has recently reported the cumulated prevalence of schizophrenia to be 24% in adolescence and 41% in adulthood.2 Studies of patients with schizophrenia find that 22q11.2 deletion accounts for approximately 0.3% of the cases. Despite massive efforts there is still no coherent understanding of the etiology of schizophrenia -a highly heritable heterogeneous disorder with strong environmental influence. 4,5 Several neurotransmitters are implicated in the disorder: glutamate, 6 γ-aminobutyric acid (GABA), 7 dopamine (DA) 8 and acetylcholine signalling 9 have all been highlighted in the disease etiology and manifestation. The cognitive impairment and negative symptomatology have been related to dysfunction in regulation of glutamate-GABA transmission leading to excitatory-inhibitory imbalances.7 Like in individuals with schizophrenia, 10,11 cognition 12 and information processing is disrupted in children with 22q11.2 deletion, in whom schizophrenia has not (yet) developed.13,14 Given the highly increased risk for schizophrenia and the phenotypic overlap between schizophrenia and the 22q11.2DS, studying the consequence of the 22q11.2 deletion provides a unique opportunity to add to the understanding of the Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neuro developmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated postpubertal N-methyl-d-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it...

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 Deletion Syndrome

“…The N1 response was diminished for both groups at the fastest presentation rate, but larger for the 22q11.2DS group at the slowest presentation rate. Increased auditory evoked potentials have been described in a 22q11.2DS mouse model: Loudness dependent amplitudes were enlarged in mice with the deletion (89). Likewise, two human studies looking at auditory processing in 22q11.2DS showed enhanced responses (76,90).…”

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.…”

Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

“…Additionally, these mice displayed altered social behavior similar to changes seen in ASD patients [13][14][15] . Df(h22q11)/+ mice displayed a decrease in pre-pulse inhibition and displayed acquired acoustic startle response similar to that seen in SCZ patients 16,22 , which could not be rescued by the antipsychotic drugs haloperidol or clozapine 16 commonly used to treat SCZ 23 . While the three mouse models all present neuropsychiatric disease relevant phenotypes, there is substantial phenotypic variability between them, consistent with the individuals carrying these CNVs who present with different diagnoses [24][25][26] .…”

“…To address whether specific genetic variants imparting major risk for schizophrenia or ASD converge at the molecular level, we leveraged three previously published mouse models with CNVs carrying significant risk for these disorders, Df(h15q13)/+ [13][14][15] , Df(h22q11)/+ 16 , and Df(h1q21)/+ 17 , which harbor the 15q13.3 deletion 18 , 22q11.2 deletion 19 , and 1q21.1 deletion 2 respectively. These three models have strong construct validity as they all harbor deletions of regions homologous to those found in human deletions associated with SCZ and ASD 2,9,19 .…”