Abstract
Background
22q11.2 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.
Methods
To 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.
Results
22qDS 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.
Conclusions
These 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.
Keywords
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Article info
Publication history
Published online: May 18, 2020
Accepted:
April 28,
2020
Received in revised form:
April 9,
2020
Received:
January 21,
2020
Identification
Copyright
© 2020 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Circuit-Based Interventions for the Treatment of Behaviors Relevant to SchizophreniaBiological PsychiatryVol. 88Issue 9
- PreviewAberrant hippocampal structure and function has been implicated in a variety of psychiatric disorders; however, the specific hippocampal circuits contributing to discrete symptom domains have not been extensively evaluated. The hippocampus has long been associated with the consolidation of declarative memory where dysfunction leads to amnesia (1); however, it is also intimately associated with emotion and stress responsivity where aberrant activity is associated with disorders such as schizophrenia and depression (2,3).
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