Dataset Information

Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome.

ABSTRACT: Several neuropsychiatric disorders are associated with cognitive and social dysfunction. Postmortem studies of patients with schizophrenia have revealed specific changes in area CA2, a long-overlooked region of the hippocampus recently found to be critical for social memory formation. To examine how area CA2 is altered in psychiatric illness, we used the Df(16)A(+/-) mouse model of the 22q11.2 microdeletion, a genetic risk factor for developing several neuropsychiatric disorders, including schizophrenia. We report several age-dependent CA2 alterations: a decrease in the density of parvalbumin-expressing interneurons, a reduction in the amount of feedforward inhibition, and a change in CA2 pyramidal-neuron intrinsic properties. Furthermore, we found that area CA2 is less plastic in Df(16)A(+/-) mice, making it nearly impossible to evoke action potential firing in CA2 pyramidal neurons. Finally, we show that Df(16)A(+/-) mice display impaired social cognition, providing a potential mechanism and a neural substrate for this impairment in psychiatric disorders.

SUBMITTER: Piskorowski RA

PROVIDER: S-EPMC4706988 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome.

Piskorowski Rebecca A RA Nasrallah Kaoutsar K Diamantopoulou Anastasia A Mukai Jun J Hassan Sami I SI Siegelbaum Steven A SA Gogos Joseph A JA Chevaleyre Vivien V

Neuron 20160101 1

Several neuropsychiatric disorders are associated with cognitive and social dysfunction. Postmortem studies of patients with schizophrenia have revealed specific changes in area CA2, a long-overlooked region of the hippocampus recently found to be critical for social memory formation. To examine how area CA2 is altered in psychiatric illness, we used the Df(16)A(+/-) mouse model of the 22q11.2 microdeletion, a genetic risk factor for developing several neuropsychiatric disorders, including schiz ...[more]

PMID: 26748091

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Project description:Background22q11.2 deletion syndrome (22qDS) manifests with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency make 22qDS symptoms particularly difficult to manage with traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored whether managing this aberrant activity in adults could be a therapeutically beneficial strategy.MethodsTo assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific subcircuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion.Results22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected memory deficits and did so in a regionally specific manner: ventrally targeted constructs rescued only social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally specific manner.ConclusionsThese data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove to be an effective therapeutic for treatment-resistant symptoms of mental illness.

Project description:Background22q11.2 deletion syndrome (22q11DS) is a common recurrent neurogenetic condition associated with elevated risk for developmental neuropsychiatric disorders and intellectual disability. Children and adults with 22q11DS often exhibit marked social impairment as well as neurocognitive deficits, and have elevated rates of both autism spectrum disorder (ASD) and psychosis. However, the relationship between the basic processes of social cognition and cognitive ability has not been well studied in 22q11DS. Here, we examined differences in social cognition in 22q11DS, relative to multiple groups of idiopathic neuropsychiatric disorders, and typically developing healthy controls (HC). Additionally, we examined differences in intellectual functioning and its relationship to social cognitive abilities. Finally, we examined the relationship between social cognitive abilities and real-world social behavior.MethodsWe examined social cognition and intellectual functioning in 273 participants (mean age = 17.74 ± 5.18% female = 44.3%): 50 with 22q11DS, 49 youth with first episode psychosis (FEP), 48 at clinical high-risk (CHR) for psychosis, 24 participants with ASD, and 102 HC. Social cognition was assessed using The Awareness of Social Inference Test (TASIT), while reciprocal social behavior was assessed via parent/caregiver ratings on the Social Responsiveness Scale (SRS). Participants were also administered the Wechsler Abbreviated Scale of Intelligence, 2nd edition (WASI-II) to assess intellectual functioning.ResultsThe 22q11DS group exhibited significantly lower social cognitive abilities compared to CHR, FEP, and HC groups after controlling for intellectual functioning, but not in comparison to the ASD group. Significant positive correlations were found between social cognition, as measured by the TASIT and IQ across groups. In contrast, no significant relationships were found between TASIT and real-world social behavior (SRS) for any group.ConclusionsOur findings indicate social cognitive deficits are more prominent in 22q11DS than idiopathic neuropsychiatric conditions across the age range, even after adjusting for global intellectual function. These results contribute to our understanding of the intellectual and social vulnerabilities of 22q11DS in comparison to idiopathic neuropsychiatric disorders. Our findings of robust associations between intellectual ability and social cognition emphasizes the importance of accounting for neurocognitive deficits in social skills interventions and tailoring these existing treatment models for 22q11DS and other populations with intellectual impairment.

Dataset Information

Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome.

Publications

Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome.

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