Restoring wild type-like network dynamics and behaviour during adulthood in a mouse model of schizophrenia

Abstract

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioural traits relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. Here we studied an animal model of the 22q11 deletion syndrome, which is the highest genetic risk to develop the pathology. We report a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches is sufficient to restore wild type-like network dynamics and behaviour during adulthood. In conclusion, our data provide mechanistic insights underlying network dysfunction relevant to schizophrenia and demonstrate the potential of reverse engineering in fostering new therapeutic strategies to alleviate the burden of neurodevelopmental disorders.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/151795 doi: bioRxiv preprint first posted online 3 Main textAlterations of network dynamics have been proposed to be instrumental in schizophrenia [1][2][3] . A specific population of inhibitory neurons, the parvalbumin interneurons (PVIs), plays a key role in regulating network dynamics 4-7 and may be involved in the pathology [8][9][10][11] . Although specific manipulations of PVI can reproduce behavioural phenotypes relevant to schizophrenia in rodents 12,13 , it remains unclear whether PVI dysfunction is causally linked to network dysfunction and pathological behaviour associated with schizophrenia. More importantly, it is not known whether manipulating PVI could restore altered physiology.Among various genetic alterations, the specific deletion of ~30 genes on chromosome 22 that leads to the 22q11 deletion syndrome (22q11DS), is the highest identified genetic risk to develop schizophrenia 14,15 . We used a genetically engineered mouse bearing a hemizygous deletion on chromosome 16, termed Lgdel/+, which replicates the chromosomal alteration of the human 22q11DS 16 . In the CA1 area of the hippocampus, mouse models of 22q11DS differ from wild-type (WT) animals regarding their structural [17][18][19] and electrophysiological properties 20 , and their functional connectivity with distant brain areas 3 . We first tested whether those differences were accompanied by intrinsic differences in network dynamics. Neural activity was monitored in hippocampal slices using the genetically encoded calcium indicator GCaMP6s expressed by CA1 neurons following adeno-associated viral (AAV) vector transfection (Fig. 1a,b). Network dynamics were induced by bath application of carbachol (50 µM), which triggered spontaneous calcium activity in individual neurons of wild type (WT) mice 21,22 (Fig. 1c,d). Likewise, individual CA1neurons of Lgdel/+ mice exhibited spontaneous calcium activity during the duration ...

Modular, Circuit-Based Interventions Rescue Hippocampal-Dependent Social and Spatial Memory in a 22q11.2 Deletion Syndrome Mouse Model

“…Recruiting the dorsal hM4Di (1 mg/kg CNO) disrupted SOR performance (1.0 ± 10.3%; p Saline vCNO =0.0225, Dunnett's correction), but recruiting the ventral KORD (1 mg/kg SB) had no significant effect (25.7 ± 10.1%; p Saline vSB =0.7632, Dunnett's). Meanwhile, the 22q cohort demonstrated a marked deficit in SOR performance (−7.8 ± 8.5%; RM one-way ANOVA F (2,18) =6.603, p=0.0071; Fig 5D), which is consistent with previous reports of dorsal hippocampal dysfunction, particularly hyperexcitability in CA1, in similar 22q models (35,36,38,39). Recruiting the dorsal hM4Di rescued their ability to discriminate (26.0 ± 9.4%; p Saline vCNO =0.0105, Dunnett's correction), while ventral KORD recruitment had no effect (−7.8 ± 10.5%; p Saline vSB =>0.9999, Dunnett's).…”

“…This modest EPSP amplitude increase coupled with the striking EPSP propagation increase may indicate an interneuronopathy, which has been found in multiple hippocampal regions of 22q mouse models (34)(35)(36). These data suggest that a hyperexcitable circuit phenotype could be responsible for the social memory behavioral deficit.…”

“…We applied the same approach to the dorsal hippocampus to examine if this type of circuitbased intervention can effect improvement in other forms of cognition, in this case spatial memory (Fig 5C). Dorsal hippocampal dysregulation in areas CA2 (34) and CA1 (35,36,38,39) have been characterized previously with multiple lines of evidence showing disease-associated hyperexcitability. Thus, we recruited inhibitory DREADDs in CA1 pyramidal cells, rescuing spatial discrimination performance in the 22q mice (Fig 5D).…”

“…Multiple groups have reported dorsal hippocampal dysregulation in 22q models using varying investigative strategies and have linked this phenotype to hippocampal-dependent cognitive deficits (34)(35)(36)38,39). Thus, to examine if chemogenetic circuit modulation could manage other symptoms, we made use of a second eloquent circuit-behavior: spatial object recognition (SOR; Fig 5C ), a non-aversive dorsal hippocampal-dependent task (30,31,40).…”

Long-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model

“…Supporting the notion that schizophrenia is linked to deficits in the recruitment of PV+ INs in the vH and medial prefrontal cortex (mPFC) through excitation, closely comparable observations have been made in experimentally accessible genetic models of schizophrenia in rodents. These include mice carrying mutations in the gene DISC1 (Hikida et al, 2007;Borkowska et al, 2016;Cardarelli et al, 2018) and mice with chromosome 16 deletions that mimic 22Q11 deletion syndrome (Df(16)A(+/À) and LgDel +/À mice; Arguello and Gogos, 2010;Karayiorgou et al, 2010;Meechan et al, 2015;Marissal et al, 2018); i.e., de novo autosomal dominant microdeletions that lead to full-blown schizophrenia in about 24% of affected adults (general population, about 1%). PV neuron dysfunctions observed in mouse models of schizophrenia include deficits in PV and GAD67 expression levels and in PV neuron recruitment (Sigurdsson et al, 2010;Belforte et al, 2010;Volman et al, 2011;Enomoto et al, 2011;Phillips et al, 2012;Thomases et al, 2013;Del Pino et al, 2013;Cho et al, 2015;Du and Grace, 2016;Hamm et al, 2017;Marissal et al, 2018).…”