Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate GeneCNTNAP2

Abstract

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.

GARLH Family Proteins Stabilize GABAA Receptors at Synapses

“…In this condition, a 90% reduction in LH4 expression was observed in hippocampi expressing two distinct sgRNAs against LH4 (sgLH4-1 and -2) (Figure S4A). To examine eIPSCs, we placed a stimulating pipette in the middle of the stratum pyramidale 150 μm away from the recorded cell (Jurgensen and Castillo, 2015). IPSCs were elicited upon stimulation and the eIPSC amplitude was saturated at 24 μA in CA1 neurons expressing sgLH4-1 (Figure 8A).…”

Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2 -deficient mice

“…Future studies are required to explore whether E:I imbalance in other brain regions, such as sensory associative areas, striatum, and hippocampus (44), may be involved in the emergence of behavioral phenotypes in the CNTNAP2 KO mice and whether similar pathophysiological mechanisms occur in other genetic models of autism. These studies will be critical to form a unified mechanistic and translational understanding of the neurons and circuits that underlie autism spectrum disorders.…”

The Role of Interneurons in Autism and Tourette Syndrome

“…This rodent model is characterized by asynchronous cortical neuronal firing, as well as a strong reduction in the number of GABAergic INs in the somatosensory cortex and striatum (with a highest reduction in the PV+ subtype). Furthermore, it has been shown that knockout of this gene affects spine density, glutamatergic receptor trafficking and perisomatic inhibition [73, 74]. In this sense, the pharmacological model of ASD based on prenatal exposure to valproate also showed a reduction of PV at the levels of protein, mRNA and cell number [75].…”