Joshua G. Corbin

Sonic Hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches

To directly test the requirement for hedgehog signaling in the telencephalon from early neurogenesis, we examined conditional null alleles of both the Sonic hedgehog and Smoothened genes. While the removal of Shh signaling in these animals resulted in only minor patterning abnormalities, the number of neural progenitors in both the postnatal subventricular zone and hippocampus was dramatically reduced. In the subventricular zone, this was partially attributable to a marked increase in programmed cell death. Consistent with Hedgehog signaling being required for the maintenance of stem cell niches in the adult brain, progenitors from the subventricular zone of floxed Smo animals formed significantly fewer neurospheres. The loss of hedgehog signaling also resulted in abnormalities in the dentate gyrus and olfactory bulb. Furthermore, stimulation of the hedgehog pathway in the mature brain resulted in elevated proliferation in telencephalic progenitors. These results suggest that hedgehog signaling is required to maintain progenitor cells in the postnatal telencephalon.

The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations

During development, the mammalian ventral telencephalon is comprised of three major proliferative zones: the medial (MGE), lateral (LGE) and caudal (CGE) ganglionic eminences. Through gene expression studies, in vitro migration assays, genetic mutant analysis and in vivo fate mapping in mice, we found that the CGE is a progenitor region that is distinct from both the MGE and LGE. Notably, CGE cells showed a unique in vivo pattern of migration, and the CGE contributed cells to nuclei distinct from those populated by the MGE and LGE. Moreover, we report that the migratory fate of cells from the CGE is intrinsically determined by embryonic day 13.5 (E13.5). Together, these results provide the first insights into the development and fate of the CGE.

The Temporal and Spatial Origins of Cortical Interneurons Predict Their Physiological Subtype

Interneurons of the cerebral cortex represent a heterogeneous population of cells with important roles in network function. At present, little is known about how these neurons are specified in the developing telencephalon. To explore whether this diversity is established in the early progenitor populations, we conducted in utero fate-mapping of the mouse medial and caudal ganglionic eminences (MGE and CGE, respectively), from which most cortical interneurons arise. Mature interneuron subtypes were assessed by electrophysiological and immunological analysis, as well as by morphological reconstruction. At E13.5, the MGE gives rise to fast-spiking (FS) interneurons, whereas the CGE generates predominantly regular-spiking interneurons (RSNP). Later at E15.5, the CGE produces RSNP classes distinct from those generated from the E13.5 CGE. Thus, we provide evidence that the spatial and temporal origin of interneuron precursors in the developing telencephalic eminences predicts the intrinsic physiological properties of mature interneurons.

Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain

During development of the mammalian telencephalon, cells migrate via diverse pathways to reach their final destinations. In the developing neocortex, projection neurons are generated from cells that migrate radially from the underlying ventricular zone. In contrast, subsets of cells that populate the ventral piriform cortex and olfactory bulb reach these sites by migrating long distances. Additionally, it has been recently established that cells migrate tangentially from the ventral ganglionic eminences to the developing cortex. These tangentially migrating cells are a significant source of cortical interneurons and possibly other cell types such as oligodendrocytes. Here we summarize the known routes of migration in the developing telencephalon, with a particular focus on tangential migration. We also review recent genetic and transplantation studies that have given greater insight into the understanding of these processes and the molecular cues that may guide these migrating cells.

Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potential-dependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.

Targeted CNS Expression of Interferon-γ in Transgenic Mice Leads to Hypomyelination, Reactive Gliosis, and Abnormal Cerebellar Development

Circumstantial and experimental evidence has implicated the immune cytokine interferon-gamma (IFN-gamma) as a key mediator in the pathological changes that are observed in many demyelinating disorders, including the most common human demyelinating disease, multiple sclerosis. To produce an animal model with which to study the effects of IFN-gamma on the CNS, we have generated transgenic mice in which the expression of IFN-gamma has been placed under the transcriptional control of the myelin basic protein (MBP) gene. Transgenic mice generated with this construct have a shaking/shivering phenotype that is similar to that observed in naturally occurring mouse models of hypomyelination (e.g., shiverer, jimpy, quaking), and these transgenic animals have dramatically less CNS myelin than control animals. Reactive gliosis and increased macrophage/microglial F4/80 immunostaining were also observed. Additionally, major histocompatibility complex (MHC) class I and class II mRNA levels were increased in the CNS of MBP/IFN-gamma transgenic mice, and the increase in MHC class I mRNA expression was detected in both white and gray matter regions. Furthermore, cerebellar granule cell migration was abnormal in these animals. These results strongly support the hypothesis that IFN-gamma is a key effector molecule in immune-mediated demyelinating disorders and indicate that the presence of this cytokine in the CNS may also disrupt the developing nervous system.

Control of segment-like patterns of gene expression in the mouse cerebellum.

A Purkinje cell-specific transgene, L7-lacZ, is expressed in a series of parasagitally oriented stripes in the mouse cerebellum. This banding pattern can be perturbed by promoter mutation, showing that a combination of positive and negative control elements contributes to the temporal and spatial map of L7 gene expression. In addition to the parasagittal stripes, certain mutations reveal Purkinje cells organized into compartments oriented in the transverse plane of the cerebellum. Transcription factors of the POU or homeobox families appear to be involved in controlling L7 expression in the transverse orientation. Strikingly, some of the domains of gene expression revealed by the mutations appear to correspond to functional compartments of Purkinje cells, thereby suggesting an underlying genetic principle used to orchestrate functional organization in the nervous system.

The effects of interferon-γ on the central nervous system

Interferon-gamma (IFN-γ) is a pleotropic cytokine released by T-lymphocytes and natural killer cells. Normally, these cells do not traverse the blood-brain barrier at appreciable levels and, as such, IFN-γ is generally undetectable within the central nervous system (CNS). Nevertheless, in response to CNS infections, as well as during certain disorders in which the CNS is affected, T-cell traffic across the blood-brain barrier increases considerably, thereby exposing neuronal and glial cells to the potent effects of IFN-γ. A large portion of this article is devoted to the substantial circumstantial and experimental evidence that suggests that IFN-γ plays an important role in the pathogenesis of the demyelinating disorder multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Moreover, the biochemical and physiological effects of IFN-γ are discussed in the context of the potential consequences of such activities on the developing and mature nervous systems.

Parsing the prosencephalon

The forebrain, or prosencephalon, consists of the diencephalon and the telencephalon. The diencephalon is the conduit for ascending sensory information, whereas the telencephalon is the highest-order processor of neural function, and is consequently the most complex region of the nervous system. In this review, we discuss how fate restrictions, starting from the induction of neural character, result in the sequential specification of anterior neural tissue, forebrain and telencephalon, and finally dorsoventral patterning. Rather than relying on novel signalling pathways, the complexity of the mature brain seems to result from the unique ordering of signals used widely during development.

Developmental Origin of PreBötzinger Complex Respiratory Neurons

A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the “core” of preBötC SST+/NK1R+/SST 2a receptor+ (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST+ neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R+/SST+ neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo.