Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.

In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.

Tonic GABAergic control of mouse dentate granule cells during postnatal development.

The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABA(A) receptors containing α(5)- and δ-subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus.

Compensatory increase in P/Q-calcium current-mediated synaptic transmission following chronic block of N-type channels.

Synaptic transmission is triggered by presynaptic calcium influx through voltage-gated calcium channels. Axon terminals of central neurons express a diverse set of homologous calcium channels, giving rise to P/Q-, N-, and R-type calcium currents. The relative contribution of these components to presynaptic calcium signalling is heterogeneous and incompletely understood. Here we report that chronic block of N-type calcium channels in developing cultured rat hippocampal neurons leads to a compensatory up-regulation of P/Q-type calcium currents. This increase was measured directly by recording whole-cell calcium currents as well as in spontaneous inhibitory postsynaptic currents, indicating a global functional up-regulation of the P/Q-component. In contrast, immunocytochemical stainings as well as quantitative real-time PCR analysis did not reveal an increased expression of Ca(v) 2.1, the underlying calcium channel alpha-subunit. We conclude that developing hippocampal neurons can compensate for the loss of one calcium current component by up-regulation of alternative isoforms at the post-translational level.

Functional maturation of developing interneurons in the molecular layer of mouse dentate gyrus.

The dentate gyrus is the main target for cortical inputs to the hippocampal formation and is particularly strongly controlled by synaptic inhibition. Many GABAergic interneurons migrate from the dentate molecular layer towards their final position in the hilus during the first two postnatal weeks. During this critical period of development we monitored the intrinsic and synaptic properties of developing interneurons in the molecular layer of mouse hippocampal slices. We focussed on multipolar cells in the middle portion of the molecular layer. With increasing age, input resistance decreased and action potential waveform changed to larger amplitude and shorter duration. Repetitive spiking was scarce at early stages, while trains of action potentials could be readily elicited after the first postnatal week. At all ages, we observed spontaneous postsynaptic currents which were almost exclusively GABA(A) receptor-mediated and increased in frequency with age. All developmental changes in intrinsic and synaptic properties occurred between p 6-8 and p 9-11, indicating a rapid functional maturation at the end of the first postnatal week. Parallel immunohistochemical experiments revealed that calretinin positive cells formed the major part of developing interneurons in the middle molecular layer. Together, the data shows a rapid functional maturation of intrinsic and synaptic properties of interneurons in the dentate molecular layer and an early integration into synaptic networks with clear prevalence of inhibitory synaptic inputs.