ABSTRACT
ARID1B, a chromatin remodeler, is strongly implicated in autism spectrum disorders (ASD). Two previous studies on Arid1b-mutant mice with the same exon 5 deletion in different genetic backgrounds revealed distinct synaptic phenotypes underlying the behavioral abnormalities: The first paper reported decreased inhibitory synaptic transmission in layer 5 pyramidal neurons in the medial prefrontal cortex (mPFC) region of the heterozygous Arid1b-mutant (Arid1b+/-) brain without changes in excitatory synaptic transmission. In the second paper, in contrast, we did not observe any inhibitory synaptic change in layer 5 mPFC pyramidal neurons, but instead saw decreased excitatory synaptic transmission in layer 2/3 mPFC pyramidal neurons without any inhibitory synaptic change. In the present report, we show that when we changed the genetic background of Arid1b+/- mice from C57BL/6 N to C57BL/6 J, to mimic the mutant mice of the first paper, we observed both the decreased inhibitory synaptic transmission in layer 5 mPFC pyramidal neurons reported in the first paper, and the decreased excitatory synaptic transmission in mPFC layer 2/3 pyramidal neurons reported in the second paper. These results suggest that genetic background can be a key determinant of the inhibitory synaptic phenotype in Arid1b-mutant mice while having minimal effects on the excitatory synaptic phenotype.
ABSTRACT
Subacute systemic treatment with 3-nitropropionic acid (3-NP) causes specific lesions in the cortex and the striatum, and Huntington's disease behavioral phenotypes in rats. We investigated differentially expressed genes in the striatum, and examined status of a highly expressed huntingtin interacting protein, profilin 2 (Pfn2) in relation to 3-NP-induced striatal neurodegeneration, employing both in vivo animal model and in vitro primary striatal neuronal cultures. Golgi staining of 3-NP-treated rat brain revealed significantly altered dendritic spine morphology and decreased spine density in the cortex and the striatum, as compared to the control. We employed suppression subtractive hybridization (SSH) method to screen differentially expressed genes during striatal neurodegeneration in these animals. Forward and reverse SSH provided a library of 188 clones, which were used for reverse northern dot blot analysis to identify greatly altered striatal-specific genes. Sequence analysis of the clones identified 23 genes, expressions of which were ⩾1.5-fold changed (16 up-regulated) in the striatum of 3-NP-treated rats. Immunoprecipitation assay showed decreased binding of Pfn2 with ß-actin, the level of which remained unaffected in the striata and cortices of 3-NP-treated rats. Primary cultures of striatal glutamic acid decarboxylase-65/67 immunopositive GABAergic neurons revealed loss of co-existence of Pfn2 and ß-actin in fluorescence imaging studies following 3-NP treatment for 24h. Since Pfn2 is known to regulate dendritic spine dynamics by interacting with ß-actin, the reduction in its binding affinity to Pfn2 following 3-NP neurotoxic insult, and the accompanying aberrations of the dendritic spine structure and loss of spine density in striatal neurons suggest that Pfn2 may be involved in neurodegeneration in 3-NP-treated rat model of HD.