Modulation of Apoptosis Controls Inhibitory Interneuron Number in the Cortex.

Cortical networks are composed of excitatory projection neurons and inhibitory interneurons. Finding the right balance between the two is important for controlling overall cortical excitation and network dynamics. However, it is unclear how the correct number of cortical interneurons (CIs) is established in the mammalian forebrain. CIs are generated in excess from basal forebrain progenitors, and their final numbers are adjusted via an intrinsically determined program of apoptosis that takes place during an early postnatal window. Here, we provide evidence that the extent of CI apoptosis during this critical period is plastic and cell-type specific and can be reduced in a cell-autonomous manner by acute increases in neuronal activity. We propose that the physiological state of the emerging neural network controls the activity levels of local CIs to modulate their numbers in a homeostatic manner.

The LIM homeodomain protein Lhx6 regulates maturation of interneurons and network excitability in the mammalian cortex.

Deletion of LIM homeodomain transcription factor-encoding Lhx6 gene in mice results in defective tangential migration of cortical interneurons and failure of differentiation of the somatostatin (Sst)- and parvalbumin (Pva)-expressing subtypes. Here, we characterize a novel hypomorphic allele of Lhx6 and demonstrate that reduced activity of this locus leads to widespread differentiation defects in Sst(+) interneurons, but relatively minor and localized changes in Pva(+) interneurons. The reduction in the number of Sst-expressing cells was not associated with a loss of interneurons, because the migration and number of Lhx6-expressing interneurons and expression of characteristic molecular markers, such as calretinin or Neuropeptide Y, were not affected in Lhx6 hypomorphic mice. Consistent with a selective deficit in the differentiation of Sst(+) interneurons in the CA1 subfield of the hippocampus, we observed reduced expression of metabotropic Glutamate Receptor 1 in the stratum oriens and characteristic changes in dendritic inhibition, but normal inhibitory input onto the somatic compartment of CA1 pyramidal cells. Moreover, Lhx6 hypomorphs show behavioral, histological, and electroencephalographic signs of recurrent seizure activity, starting from early adulthood. These results demonstrate that Lhx6 plays an important role in the maturation of cortical interneurons and the formation of inhibitory circuits in the mammalian cortex.

Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes.

The cerebral cortex contains two main neuronal cell populations, the excitatory glutamatergic (pyramidal) neurons and the inhibitory interneurons, which synthesize GABA and constitute 20-30% of all cortical neurons. In contrast to the mostly homogeneous population of projection neurons, cortical interneurons are characterized by remarkable morphological, molecular, and functional diversity. Among the markers that have been used to classify cortical interneurons are the calcium-binding proteins parvalbumin and calretinin and the neuropeptide somatostatin, which in rodents identify mostly nonoverlapping interneuron subpopulations. Pyramidal neurons are born during embryogenesis in the ventricular zone of the dorsal telencephalon, whereas cortical interneurons are generated in the subpallium and reach the cortex by tangential migration. On completion of tangential migration, cortical interneurons switch to a radial mode of migration and enter the cortical plate. Although the mechanisms that control the generation of interneuron diversity are currently unknown, it has been proposed that their site of origin in the ventral forebrain determines their specification into defined neurochemical subgroups. Here, we show that Lhx6, a gene induced in the medial ganglionic eminence and maintained in parvalbumin- and somatostatin-positive interneurons, is required for the specification of these neuronal subtypes in the neocortex and the hippocampus. We also show that Lhx6 activity is required for the normal tangential and radial migration of GABAergic interneurons in the cortex.

High expression levels of p27 correlate with lymph node status in a subset of advanced invasive breast carcinomas: relation to E-cadherin alterations, proliferative activity, and ploidy of the tumors.

BACKGROUND: The cyclin-dependent kinase inhibitor p27 plays a central role in cell cycle progression and is deregulated in breast carcinomas. Although its levels are inversely associated with tumor proliferation, overexpression of p27 has been reported in a subset of rapidly proliferating breast carcinoma cell lines. METHODS: p27 levels were determined by immunohistochemistry in a series of 52 sporadic invasive breast carcinomas consisting of 47 ductal, 2 lobular, and 3 mixed; most tumors were Grade 2 or 3 (46 of 52) and Tumor Node Metastasis (TNM) Stage II-IV (46 of 52). E-cadherin expression and its gene alterations at 16q22.1 were also studied, because in vitro evidence suggests a biologic association between p27 and E-cadherin-mediated growth suppression. RESULTS: The mean p27 labeling index (LI; percentage of p27 positive tumor cells) was 33.3% +/- 25.3% (range, 0.1-85%). High p27 levels (p27 LI, > 50%) were observed in 14 (26.9%) of 52 carcinomas and were significantly associated with metastatic disease in axillary lymph nodes (14 of 33 vs. 0 of 19; P = 0.0007 by Fisher exact test). In addition, p27 LI was higher in the group of lymph node positive vs. lymph node negative tumors (mean p27 LI, 40.9% vs. 20.1%; P = 0.008 by Mann-Whitney test). Reduced or absent E-cadherin expression was found in 27 of 45 (60%) informative cases. Allelic imbalance of the 16q22.1 locus was found in 14 (27.5%) of 51 cases by using the microsatellite markers D16S503, D16S752, and D16S512. p27 LI and E-cadherin alterations were not statistically related. CONCLUSIONS: In summary, high p27 levels detected in a subset of advanced breast carcinomas correlate with lymph node metastasis, suggesting that other mechanisms may bypass the cell cycle inhibitory role of p27 and provide growth advantage in these tumors.