Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/- animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73-/- animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73-/- animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that DeltaNp73 is essential for survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.

We determined the neurogenesis characteristics of a distinct subclass of rat striatum gamma-aminobutyric acidergic (GABAergic) interneurons expressing the calcium-binding protein calretinin (CR). Timed-pregnant rats were given an intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU), a marker of cell proliferation, on designated days between embryonic day 12 (E12) and E21. CR-immunoreactive (-IR) neurons and BrdU-positive nuclei were labeled in the adult neostriatum by double immunohistochemistry, and the proportion of double-labeled cells was quantified. CR-IR interneurons of the neostriatum show maximum birth rates (>10% double labeling) between E14 and E17, with a peak at E15. CR-IR interneurons occupying the lateral half of the neostriatum become postmitotic prior to medial neurons. In the precomissural neostriatum, the earliest-born neurons occupy the lateral quadrants and the latest-born neurons occupy the dorsomedial sector. No significant rostrocaudal neurogenesis gradient is observed. CR-IR neurons make up 0.5% of the striatal population and are localized in both the patch and the matrix compartments. CR-IR neurons of the patch compartment are born early (E13-15), with later-born neurons (E16-18) populating mainly the matrix compartment. CR-IR cells of the neostriatum are a distinct subclass of interneurons that are born at an intermediate time during striatal development and share common neurogenesis characteristics with other interneurons and projection neurons produced in the ventral telencephalon.

No abstract

Recent studies have proposed that glutamate corelease by mesostriatal dopamine (DA) neurons regulates behavioral activation by psychostimulants. How and when glutamate release by DA neurons might play this role remains unclear. Considering evidence for early expression of the type 2 vesicular glutamate transporter in mesencephalic DA neurons, we hypothesized that this cophenotype is particularly important during development. Using a conditional gene knock-out approach to selectively disrupt the Vglut2 gene in mouse DA neurons, we obtained in vitro and in vivo evidence for reduced growth and survival of mesencephalic DA neurons, associated with a decrease in the density of DA innervation in the nucleus accumbens, reduced activity-dependent DA release, and impaired motor behavior. These findings provide strong evidence for a functional role of the glutamatergic cophenotype in the development of mesencephalic DA neurons, opening new perspectives into the pathophysiology of neurodegenerative disorders involving the mesostriatal DA system.

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

No abstract

Pioneering work indicates that the final position of neurons in specific layers of the mammalian cerebral cortex is determined primarily by birthdate. Glutamatergic projection neurons are born in the cortical proliferative zones of the dorsal telencephalon, and follow an "inside-out" neurogenesis gradient: later-born cohorts migrate radially past earlier-born neurons to populate more superficial layers. GABAergic interneurons, the major source of cortical inhibition, comprise a heterogeneous population and are produced in proliferative zones of the ventral telencephalon. Mechanisms by which interneuron subclasses find appropriate layer-specific cortical addresses remain largely unexplored. Major cortical interneuron subclasses can be identified based on expression of distinct calcium-binding proteins including parvalbumin, calretinin, or calbindin. We determined whether cortical layer-patterning of interneurons is dependent on phenotype. Parvalbumin-positive interneurons populate cortical layers with an inside-out gradient, and birthdate is isochronous to projection neurons in the same layers. In contrast, another major GABAergic subtype, labeled using calretinin, populates the cerebral cortex using an opposite "outside-in" gradient, heterochronous to neighboring neurons. In addition to birthdate, phenotype is also a determinant of cortical patterning. Discovery of a cortical subpopulation that does not follow the well-established inside-out gradient has important implications for mechanisms of layer formation in the cerebral cortex.