Abstract
One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877–888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.
Highlights
One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/ inhibitory (E/I) circuit balance during critical periods of development [4,5,6]
GABA-synthetic enzyme (GAD65 KO) in mice delays plasticity onset within the visual cortex indefinitely [7], which can be rescued at any age with benzodiazepines [8]
No significant difference in interhemispheric ratios between valproic acid (VPA)- and saline-treated mice were found in area CA1, indicating a neocortex-specific deficit
Summary
PV-cell numbers in NL-3 mutant mice were reduced >50% in the neocortex (Fig. 3). The PV-positive, large basket cells have been implicated in two functions (Fig. 4): 1) initiation of a critical period for cortical plasticity [1], and 2) generation and synchronization of gamma (γ)-oscillations in the hippocampus and neocortex [31]. Both phenomena have been suggested to be impaired in the etiology of cognitive developmental disorders such as ASD, and can strikingly both be accounted for by the common PV-cell deficit reported here
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