Diverse receptive fields in the lateral geniculate nucleus during thalamocortical development.

Most models of thalamocortical development in the visual system assume a homogeneous population of thalamic inputs to the cortex, each with concentric on- or off-center receptive fields. To test this, we made high-resolution spatial maps of receptive fields in the developing ferret lateral geniculate nucleus (LGN). Developing receptive fields (RFs), had a variety of shapes: some concentric, others elongated (like adult cortical receptive fields) and some with 'hot spots' of sensitivity. These receptive fields seemed to arise from convergence of multiple retinal afferents onto LGN neurons. We present a Hebbian model whereby imprecise retinogeniculate connections help refine geniculocortical connections, sharpening both thalamocortical topography and perhaps orientation selectivity.

Coexistence of widespread clones and large radial clones in early embryonic ferret cortex.

Cell lineage analysis in rodents has shown that the cerebral cortex is formed from both widespread and large radial clustered clones representing partly distinct lineages and producing differing cell types. Since previous cell lineage analysis of the ferret cortex using retroviral libraries showed that most neurons labeled at E33-E35 formed widespread clones, we determined whether clones labeled earlier in neurogenesis showed a greater tendency to form coherent radial clones. Clones labeled at E27-E29 occasionally consisted of widespread multineuron clones (13% of PCR-defined clones), but commonly consisted of small clusters of two to four neurons (65%). Moreover, 6/21 hemispheres contained a single, much larger (6-150 cells) radial cluster. Although large clusters were observed in 28% of experiments, they contained many neurons, accounting for 38% of retrovirally labeled cells. The large clusters showed at most few widely scattered sibling cells, either by histological analysis or by PCR analysis, suggesting that radial and widespread clones coexist but are lineally separate at early stages of corticogenesis. Coexistence of large radial and widespread neuronal clones appears to be an evolutionarily conserved mechanism for cortical neurogenesis.

CREB: a major mediator of neuronal neurotrophin responses.

Neurotrophins regulate neuronal survival, differentiation, and synaptic function. To understand how neurotrophins elicit such diverse responses, we elucidated signaling pathways by which brain-derived neurotrophic factor (BDNF) activates gene expression in cultured neurons and hippocampal slices. We found, unexpectedly, that the transcription factor cyclic AMP response element-binding protein (CREB) is an important regulator of BDNF-induced gene expression. Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at least two signaling pathways: by a calcium/calmodulin-dependent kinase IV (CaMKIV)-regulated pathway that is activated by the release of intracellular calcium and by a Ras-dependent pathway. These findings reveal a previously unrecognized, CaMK-dependent mechanism by which neurotrophins activate CREB and suggest that CREB plays a central role in mediating neurotrophin responses in neurons.

Clonal dispersion and evidence for asymmetric cell division in ferret cortex.

Cell lineage analysis with retroviral libraries suggests that clonal progeny disperse widely in rodent cortex. To determine whether widespread dispersion is a general mammalian plan and to investigate phylogenetic differences in cortical development, we analyzed cell lineage in the ferret, a carnivore and near relative of the cat. The ferret possesses a highly developed, folded cerebral cortex, characteristic of higher mammalian species. Progenitor cells of the ferret cerebral cortex were tagged with an amphotropic retroviral library encoding alkaline phosphatase, and sibling relationships were determined using the polymerase chain reaction. Neuronal clones were single neurons (52%) or large clones (48%; average, 7 neurons) containing neurons and glia in widespread cortical locations. Neuronal clones in the ferret labeled at middle to late neurogenesis (embryonic day 33-35) contained large numbers of neurons and showed little tendency to cluster. The large proportion of single neuron clones, contrasted with the large size of multicell clones, suggests that some progenitors divide asymmetrically, producing a postmitotic neuron and regenerating a multipotential cell.

Differential block of nicotinic synapses on B versus C neurones in sympathetic ganglia of frog by alpha-conotoxins MII and ImI.

1. The effects of two new acetylcholine receptor antagonists, alpha-conotoxin MII and alpha-conotoxin ImI, on nicotinic synaptic transmission in the 10th paravertebral sympathetic ganglion of the leopard frog (Rana pipiens) were examined. The preganglionic nerve was electrically stimulated (at low frequency, < or = 1 min-1, to avoid use-dependent changes) while compound action potentials of B and C neurones were monitored from the postganglionic nerve. 2. alpha-Conotoxins MII and ImI, at low micromolar concentrations, reversibly blocked both B and C waves, alpha-Conotoxin MII blocked the C wave more effectively than the B wave, whereas the potency of alpha-conotoxin ImI was opposite that of MII. The observation that nicotinic antagonists can differentially block synaptic transmission of B versus C neurones with opposite selectivities strongly suggests that these neurones possess distinct nicotinic receptors. 3. In addition to fast and slow B waves described by others. C waves with two temporally distinguishable components were present in our recordings. Each alpha-conotoxin affected fast and slow B waves similarly. Likewise, toxins did not discriminate between the two components of C waves. This suggests that all neurones within each major class (B or C) may have the same nicotinic receptors. 4. Synthetic forms of alpha-conotoxins MII and ImI were used in the present study. Their ease of synthesis and their specificities should make these toxins useful probes to investigate the various subtypes of neuronal nicotinic acetylcholine receptors.