Abstract
Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse models of ASD. We previously showed a reduced expression of GABAergic interneuron markers parvalbumin (PV) and somatostatin (SST) in the forebrain of adult mice lacking the Engrailed2 gene (En2-/- mice). Here, we extended this analysis to postnatal day (P) 30 by using in situ hybridization, immunohistochemistry, and quantitative RT-PCR to study the expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of En2-/- and wild type (WT) mice. In addition, GABA receptor subunit mRNA expression was investigated by quantitative RT-PCR in the same brain regions of P30 and adult En2-/- and WT mice. As observed in adult animals, PV and SST expression was decreased in En2-/- forebrain of P30 mice. The expression of GABA receptor subunits (including the ASD-relevant Gabrb3) was also altered in young and adult En2-/- forebrain. Our results suggest that GABAergic neurotransmission deficits are already evident at P30, confirming that neurodevelopmental defects of GABAergic interneurons occur in the En2 mouse model of ASD.
Highlights
Impaired function of GABAergic interneurons and subsequent alteration of excitation/inhibition balance in neural circuits has been implicated in neurodevelopmental disorders [1].Forebrain GABAergic interneurons originate from the ganglionic eminences of the ventral forebrain, from where they migrate and differentiate during embryonic and early postnatal development [2].Different classes of GABAergic interneurons are distinguished on the basis of their morphology, neurochemical content, intrinsic electrophysiological properties, and connectivity [3,4,5,6,7]
We first performed a morphometric analysis on dorsal hippocampal and somatosensory cortex sections stained with cresyl violet to investigate the layering of these structures in P30 wild type (WT) and
We investigated the expression of GABAergic interneuron markers in the hippocampus of P30 WT and En2-/- mice
Summary
Impaired function of GABAergic interneurons and subsequent alteration of excitation/inhibition balance in neural circuits has been implicated in neurodevelopmental disorders [1].Forebrain GABAergic interneurons originate from the ganglionic eminences of the ventral forebrain, from where they migrate and differentiate during embryonic and early postnatal development [2].Different classes of GABAergic interneurons are distinguished on the basis of their morphology, neurochemical content, intrinsic electrophysiological properties, and connectivity [3,4,5,6,7]. Impaired function of GABAergic interneurons and subsequent alteration of excitation/inhibition balance in neural circuits has been implicated in neurodevelopmental disorders [1]. Forebrain GABAergic interneurons originate from the ganglionic eminences of the ventral forebrain, from where they migrate and differentiate during embryonic and early postnatal development [2]. Defects in GABAergic neuron number and transmission have been hypothesized to contribute to autism spectrum disorders (ASD) [8,9,10]. Altered numbers of GABAergic interneurons were detected in the hippocampus of ASD subjects [11], and reduced GABA receptor density, number, and protein expression were observed in the cerebellum and cortical areas of people with ASD [12].
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