Reduced prefrontal synaptic connectivity and disturbed oscillatory population dynamics in the CNTNAP2 model of autism

Abstract

Loss of function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder (ASD) in humans and produce social deficits, repetitive behaviors, and seizures in mice. Yet, the functional effects of these mutations at the cellular and circuit level remain elusive. Using laser scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in functional excitatory and inhibitory synaptic inputs in L2/3 medial prefrontal cortex (mPFC) of Cntnap2 knock-out (KO) mice. In accordance with decreased synaptic input, KO mice displayed reduced spine and synapse densities, despite normal intrinsic excitability and dendritic complexity. To determine how this decrease in synaptic inputs alters coordination of neuronal firing patterns in vivo, we recorded mPFC local field potentials (LFP) and unit spiking in head-fixed mice during locomotion and rest. In KO mice, LFP power was not significantly altered at all tested frequencies, but inhibitory neurons showed delayed phase-firing and reduced phase-locking to delta and theta oscillations during locomotion. Excitatory neurons showed similar changes but only to delta oscillations. These findings suggest that profound ASD-related alterations in synaptic inputs can yield perturbed temporal coordination of cortical ensembles.All rights reserved. No reuse allowed without permission.

Parvalbumin Interneuron Activity Underlies Vulnerability to Post-Traumatic Stress Disorder in Autism

“…In particular, we observed a hypoactivation of the hippocampus and amygdala, as well as a hyperactivation of the mPFC. These different levels of activation are consistent with those previously reported in ASD (17,18,20) but are opposite to the patterns observed in PTSD (i.e. mPFC hypoactivation and amygdala hyperactivation (11)).…”

“…Maladaptive memory is underpinned by imbalanced neuronal activity within the prefrontal-hippocampoamygdalar network, in both mice and humans (15,16). Interestingly, the medial prefrontal cortex (mPFC), hippocampus, and amygdala have also been implicated in the pathophysiology of ASD (17)(18)(19). To uncover potential divergent mechanisms in PTSD and ASD, we mapped the brain activations induced by re-exposure to the conditioning context (Figure 2A).…”

“…Within the prefrontal-hippocampo-amygdalar network, the mPFC underpins a key function in the pathophysiology of both PTSD and ASD (16,18,22). In addition, modulating the activity of the mPFC normalizes the core symptoms of ASD (20).…”

Excitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice

“…To explore cortical mechanisms underlying ASD-related social deficits, we attempted to measure and compare neuronal firings in live wild-type (WT) and Shank2 -/mice, a mouse model of ASD 15 , engaged in social interaction. We targeted the medial prefrontal cortex (mPFC), a brain region with strong social implications 25,[47][48][49][50] .…”

CNTNAP2 is targeted to endosomes by the polarity protein PAR3

“…While CNTNAP2 and PAR3 are expressed in both excitatory and inhibitory neurons (Gao et al, ; Karayannis et al, ; Kim et al, ; Lazaro et al, ; Mo et al, ), we chose to focus on the latter as CNTNAP2 is more highly expressed in interneurons (Gao et al, ; Karayannis et al, ; Mo et al, ) and because inhibitory circuits are a critical but underexplored aspect of disease pathogenesis in neuropsychiatric disorders (Marin, ; Markram et al, ). However, PAR3 and CNTNAP2 are also expressed in excitatory neurons (Allen Brain Atlas), particularly within the postsynaptic density (Figure b, Figure S1).…”