Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.

A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. In vivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit.

To study the function of GLAST, a glutamate transporter highly expressed in the cerebellar Bergmann astrocytes, the mouse GLAST gene was inactivated. GLAST-deficient mice developed normally and could manage simple coordinated tasks, such as staying on a stationary or a slowly rotating rod, but failed more challenging task such as staying on a quickly rotating rod. Electrophysiological examination revealed that Purkinje cells in the mutant mice remained to be multiply innervated by climbing fibres even at the adult stage. We also found that oedema volumes in the mutant mice increased significantly after cerebellar injury. These results indicate that GLAST plays active roles both in the cerebellar climbing fibre synapse formation and in preventing excitotoxic cerebellar damage after acute brain injury.

The glutamate transporter GLAST is localized on the cell membrane of mature astrocytes and is also expressed in the ventricular zone of developing brains. To characterize and follow the GLAST-expressing cells during development, we examined the mouse spinal cord by in situ hybridization and immunohistochemistry. At embryonic day (E) 11 and E13, cells expressing GLAST mRNA were present only in the ventricular zone, where GLAST immunoreactivity was associated with most of the cell bodies of neuroepithelial cells. In addition, GLAST immunoreactivity was detected in radial processes running through the mantle and marginal zones. From this characteristic cytology, GLAST-expressing cells at early stages were judged to be radial glia cells. At E15, cells expressing GLAST mRNA first appeared in the mantle zone, and GLAST-immunopositive punctate or reticular protrusions were formed along the radial processes. From E18 to postnatal day (P) 7, GLAST mRNA or its immunoreactivity gradually decreased from the ventricular zone and disappeared from radial processes, whereas cells with GLAST mRNA spread all over the mantle zone and GLAST-immunopositive punctate/reticular protrusions predominated in the neuropils. At P7, GLAST-expressing cells were immunopositive for glial fibrillary acidic protein, an intermediate filament specific to astrocytes. Therefore, the glutamate transporter GLAST is expressed from radial glia through astrocytes during spinal cord development. Furthermore, the distinct changes in the cell position and morphology suggest that both the migration and transformation of radial glia cells begin in the spinal cord between E13 and E15, when the active stage of neuronal migration is over.

Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism and behaviour. They bind to G-protein-coupled receptors on the cell surface to elicit their effects. Bombesin-like peptide receptors cloned so far include, gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result of its low affinity for bombesin and its lack of an identified natural ligand. We have generated BRS-3-deficient mice in an attempt to determine the in vivo function of the receptor. Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism. They also exhibited reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. Our data suggest that BRS-3 is required for the regulation of endocrine processes and metabolism responsible for energy balance and adiposity. BRS-3-deficient mice provide a useful new model for the investigation of human obesity and associated diseases.

The Bergmann glia is composed of unipolar protoplasmic astrocytes in the cerebellar cortex. Bergmann glial cells locate their cell bodies around Purkinje cells, and extend radial or Bergmann fibers enwrapping synapses on Purkinje cell dendrites. During development, Bergmann fibers display a tight association with migrating granule cells, from which the concept of glia-guided neuronal migration has been proposed. Thus, it is widely known that the Bergmann glia is associated with granule cells in the developing cerebellum and with Purkinje cells in the adult cerebellum. As the information on how Bergmann glial cells are related structurally and functionally with differentiating Purkinje cells is quite fragmental, this issue has been investigated using cytochemical techniques for Bergmann glial cells. This review classifies the cytodifferentiation of Bergmann glial cells into four stages, that is, radial glia, migration, transformation and protoplasmic astrocytes, and then summarizes their structural relationship with Purkinje cells at each stage. The results conclude that the cytodifferentiation of Bergmann glial cells proceeds in correlation with the migration, dendritogenesis, synaptogenesis and maturation of Purkinje cells. Furthermore, morphological and molecular plasticity of this neuroglia appears to be regulated depending on the cytodifferentiation of nearby Purkinje cells. The functional relevance of this intimate neuron-glial relationship is also discussed with reference to recent studies in cell biology, cell ablation and gene knockout.

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