Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.
We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions. Accordingly, we analyzed neuronal changes that reflect previously defined 22q11DS-related alterations of cortical development in the medial anterior frontal cortex of the behaviorally characterized LgDel mice. Interneuron placement, synapse distribution, and projection neuron frequency are altered in this region. The magnitude of one of these changes, layer 2/3 projection neuron frequency, is a robust predictor of behavioral performance: it is substantially and selectively lower in animals with the most significant behavioral deficits. These results parallel correlations of volume reduction and altered connectivity in comparable cortical regions with diminished executive function in 22q11DS patients. Apparently, 22q11 deletion alters behaviorally relevant circuits in a distinct cortical region that are essential for cognitive function.
Department of Pharmacology and Physiology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
D W
DW
Meechan
Department of Psychology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
H L H
HL
Rutz
Department of Pharmacology and Physiology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
M S
MS
Fralish
Department of Pharmacology and Physiology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
T M
TM
Maynard
Department of Psychology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
L A
LA
Rothblat
Department of Pharmacology and Physiology GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA.
A-S
AS
LaMantia
D058165:22q11 Deletion Syndrome / Q000473:pathology* / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal; D003071:Cognition; D004193:Discrimination Learning; D004195:Disease Models, Animal; D056344:Executive Function; D005625:Frontal Lobe / Q000166:cytology / Q000473:pathology*; D007395:Interneurons / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D013569:Synapses / Q000473:pathology
anterior cingulate cortex; cortical circuit disorders; interneurons; projection neurons; reversal learning