Local GABAergic interneurons sculpt the activities in cortical circuits controlling excitability and timing of principal neurons. They have been implicated in the generation and control of theta/gamma frequency oscillations and in the normal development of cortical circuitry, including the regulation of neuronal proliferation and migration. Converging clinical evidence suggests that altered interneuron function may underlie the pathophysiology of major psychiatric disorders, such us schizophrenia or depression. In spite of these recent results, no pharmacological manipulations exist to specifically control in vivo activity of interneurons. To overcome this limitation we have developed a novel genetically engineered mouse strain in which Cre expression is targeted specifically to forebrain GABAergic cells. We homologously integrated Cre recombinase cDNA into the promoter region of a protein phosphatase 1 regulatory subunit in bacterial artificial chromosome (BAC), and several BAC transgenic mice were generated. One of the strains, Cre#4127, showed a selective Cre recombination pattern on a significant population of GAD67-positive cells in the cerebral cortex and hippocampus but not in other brain regions, such as thalamus and cerebellum. Immunohistochemical analyses revealed that more than 90% of the beta-Gal positive cells, after crossing with R26R-LacZ reporter line, are GAD67 positive and do not co-localize with glutamatergic neuron markers, such as TBR1 and alpha-CaMKII, suggesting that Cre recombination occurs predominantly in the forebrain GABAergic cells. Furthermore, most of the beta-Gal positive cells were parvalbumin (PV) positive while none of them were calretinin positive. Cre-mediated recombination begins from the first postnatal week, allowing early manipulation of the targeted cells. To induce ablation of the targeted cells, we crossed the Cre line with a floxed-diphtheria toxin (DT) receptor strain (provided by Drs. Ari Waisman and Thorsten Buch), in which the Cre expressing cells can be ablated upon i.p. administration of DT. In addition, to create forebrain interneuron-restricted NR1 knockout mice, Cre#4127 stain has been crossed with floxed-NR1 strains. Behavioral analysis of this strain is underway to advance our understanding of in vivo function of cortical GABAergic interneurons in relation to psychiatric-like disorders.
| Jiang, Zhihong; Rompala, Gregory R; Zhang, Shuqin et al. (2013) Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. Biol Psychiatry 73:1024-34 |
