Neurofibromatosis type 1-associated optic pathway gliomas: Current challenges and future prospects

Optic pathway glioma (OPG) occurs in as many as one-fifth of individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Generally considered low-grade and slow growing, many children with NF1-OPGs remain asymptomatic. However, due to their location within the optic pathway, ~20-30% of those harboring NF1-OPGs will experience symptoms, including progressive vision loss, proptosis, diplopia, and precocious puberty. While treatment with conventional chemotherapy is largely effective at attenuating tumor growth, it is not clear whether there is much long-term recovery of visual function. Additionally, because these tumors predominantly affect young children, there are unique challenges to NF1-OPG diagnosis, monitoring, and longitudinal management. Over the past two decades, the employment of authenticated genetically engineere

Intrinsically determined cell death of developing cortical interneurons

Cortical inhibitory circuits are formed by GABAergic interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis1-5, is that cortical interneurons are overproduced, and then following their migration into cortex, excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we have characterized the developmental cell death of mouse cortical interneurons in vivo, in vitro, and following transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax- (Bcl-2 associated X-) dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Remarkably, over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by central nervous system (CNS) neurons6-8. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Together, our findings indicate that interneuron cell death is intrinsically determined, either cell-autonomously, or through a population-autonomous competition for survival signals derived from other interneurons

Role of MGE- and CGE-derived Interneuron Subtypes in Transplant-induced Cortical Plasticity

Cortical GABAergic interneurons have been shown to play a pivotal role in ocular dominance plasticity (ODP) during the developmental critical period. GABAergic interneurons are extremely diverse, and currently it is unclear which interneuron subtypes contribute to critical period plasticity. The majority of cortical GABAergic interneurons originate from the medial and caudal ganglionic eminences (MGE and CGE, respectively). Transplanted into the visual cortex of postnatal animals, MGE-derived interneuron precursors can disperse, mature, integrate into local visual cortical circuit, and open a second window of critical-period-like plasticity. Because transplanted MGE precursor cells differentiate primarily into parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) cells, we genetically ablated PV+ or SST+ cells in the transplants and tested whether the remaining cells can induce plasticity in the recipients. Surprisingly, removing PV+ cells did not prevent MGE transplants from inducing plasticity, despite strong evidence linking PV+ interneurons to critical period plasticity. Depleting SST+ cells did not abolish transplant-induced plasticity, either, but removing both PV+ and SST+ cells eliminated plasticity. Our results show that SST+ interneurons, which are abundant and powerful inhibitors in the visual cortex but have scarcely been studied in the context of ODP, are as competent as PV+ interneurons in mediating plasticity. To investigate the contribution of other interneuron subtypes to critical period plasticity, we transplanted CGE-derived interneuron precursors into postnatal recipients. Cells from CGE transplants migrated into the visual cortex as efficiently as MGE-derived interneurons. CGE-derived precursor cells did not differentiated into PV+ or SST+ cells, but instead generated interneurons expressing diverse subtype markers such as reelin, calretinin, and vasoactive intestinal peptide. Despite successful engraftment and efficient migration, CGE-derived interneurons failed to induce plasticity. Our results demonstrate that transplanted interneuron precursors from both MGE and CGE migrate vigorously in the postnatal cortex and differentiate into a diverse panel of cortical interneuron subtypes. However, only PV+ and SST+ interneurons derived from the MGE can modify host neural circuits and reintroduce juvenile-like plasticity into the adult cortex. These findings provide important insights into the functional application of interneuron subtypes. Such information will be crucial in investigating the mechanisms of critical period plasticity and devising effective strategies of transplant therapy

Estrogen Induces IL-1β to Mediate Retinal Ganglion Cell Loss in Murine Optic Glioma

Optic pathway glioma (OPG) is a low-grade astrocytoma seen in 15-20% of children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. While not fatal, 30-50% of children with NF1-OPG exhibit retinal ganglion cell (RGC) death and vision loss, which is three times more frequent in girls. Using murine Nf1-OPG models, we previously demonstrated that estrogen acts at the level of microglia to induce RGC death. Herein, we present evidence that estrogen mediates RGC death through IL-1β

Relationship Between Cerebral Amyloid Burden and OCT Changes in Preclinical Alzheimer's Disease

Preclinical Alzheimer's disease (AD) is an early stage of AD with increased cerebral amyloid burden, measured either by cerebral spinal fluid (CSF) amyloid markers or positron imaging tomography (PET). Our previous study demonstrated enlargement of the foveal avascular zone (FAZ) of eyes from preclinical AD patients compared to controls, a feature that is stable at follow-up after 3 years. Here we present additional analysis of relationships between severity of cerebral amyloidosis and changes in retinal structure and vascularity

Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons

GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV(+)) and somatostatin-expressing (SST(+)) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV(+) cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV(+) or SST(+) interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV(+) cells but in which the majority of SST(+) interneurons were depleted. Surprisingly, transplants in which the majority of PV(+) cells were depleted induced plasticity as effectively as those containing PV(+) cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV(+) cells do not play an exclusive role in ODP; SST(+) interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV(+) and SST(+) interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair

Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity

The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV) or somatostatin (SST) interneurons from the medial ganglionic eminence (MGE) reactivates ocular dominance plasticity (ODP) in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE)-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP

Intrinsically determined cell death of developing cortical interneurons.

Cortical inhibitory circuits are formed by γ-aminobutyric acid (GABA)-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons

Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion.

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs--including the α-2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes