Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate Gene CNTNAP2.
Mutations in the human gene encoding contactin-associated protein-like 2 (CNTNAP2) have been strongly associated with autism spectrum disorders (ASDs). Cntnap2(-/-) mice recapitulate major features of ASD, including social impairment, reduced vocalizations, and repetitive behavior. In addition, Cntnap2(-/-) mice show reduced cortical neuronal synchrony and develop spontaneous seizures throughout adulthood. As suggested for other forms of ASDs, this phenotype could reflect some form of synaptic dysregulation. However, the impact of lifelong deletion of CNTNAP2 on synaptic function in the brain remains unknown. To address this issue, we have assessed excitatory and inhibitory synaptic transmission in acute hippocampal slices of Cntnap2(-/-) mice. We found that although excitatory transmission was mostly normal, inhibition onto CA1 pyramidal cells was altered in Cntnap2(-/-) mice. Specifically, putative perisomatic, but not dendritic, evoked IPSCs were significantly reduced in these mice. Whereas both inhibitory short-term plasticity and miniature IPSC frequency and amplitude were normal in Cntnap2(-/-) mice, we found an unexpected increase in the frequency of spontaneous, action potential-driven IPSCs. Altered hippocampal inhibition could account for the behavioral phenotype Cntnap2(-/-) mice present later in life. Overall, our findings that Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition while sparing excitation provide additional support for synaptic dysfunction as a common mechanism underlying ASDs.
Dominick P. Purpura Department of Neuroscience and Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York 10461.
Sofia
S
Jurgensen
Dominick P. Purpura Department of Neuroscience and Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York 10461 pablo.castillo@einstein.yu.edu.
Pablo E
PE
Castillo
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017966:Pyramidal Cells / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics
C568163:CNTNAP2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
CASPR2; E/I balance; cell adhesion; epilepsy; perisomatic inhibition; synaptopathy