1. A Sparse View of Cortical Activity
Jack Waters and Fritjof Helmchen
This week, Waters and Helmchen examined the ups and downs of neuronal activity, using in vivo whole-cell recording from L2/3 neocortical pyramidal neurons in anesthetized rats. Spontaneous activity in these cells drove 10-20 mV membrane excursions between subthreshold "Up states" and hyperpolarized "Down states." Although depolarizing excitatory synaptic potentials might be expected to open glutamate-activated ion channels and increase membrane conductance (i.e., decrease input resistance), the input resistance of layer 2/3 cells actually increased during Up states. Constant current injections confirmed a voltage-dependent increase in the membrane input resistance with depolarization, attributable to intrinsic membrane channels that cause anomalous rectification. Under the conditions of their experiments, spontaneous activity was 90% excitatory, but sparse. Using a compartmental model of L2/3 cells to control the rate of activity and synchrony of synaptic inputs, the authors predict that as few as 10 or as many as 100 activated synapses are required to fire an action potential.
2. The Transactivator Trap Screen Strikes Again
Amir H. Kashani, Zilong Qiu, Linda Jurata, Soo-Kyung Lee, Samuel Pfaff, Sandra Goebbels, Klaus-Armin Nave, and Anirvan Ghosh
Calcium often serves as a link connecting neural activity to gene transcription. Kashani et al. used a transactivator trap screen to identify mediators of calcium-dependent gene transcription, a method that previously led them to identify CREST, a calcium-regulated transcriptional activator. The authors screened pools of rat cortical cDNA library by transfection into cortical neurons and then looked for activation of a reporter gene after depolarization and calcium influx. Here they report on LMO4, a 165 aa nuclear LIM-domain-only protein that is expressed in cortex during the early postnatal period. LMO4 activation required L-type voltage-gated channels and NMDA receptors, as well as activation of calcium/calmodulin-dependent kinase IV and mitogen-activated protein kinase. LMO4 interacted with CREB (cAMP response element-binding protein) and the coactivators CLIM1 and CLIM2. Conditional deletion of lmo4 in the forebrain disrupted segregation of thalamocortical afferents into barrel domains in the somatosensory cortex.
3. An Approach to the Complexity of Neural Circuits
Jonathon Shlens, Greg D. Field, Jeffrey L. Gauthier, Matthew I. Grivich, Dumitru Petrusca, Alexander Sher, Alan M. Litke, and E. J. Chichilnisky
This week, Shlens et al. try to simplify the study of neuronal networks, a potential boon for the mathematically challenged neuroscientist. The authors examined the network of ON and OFF parasol retinal ganglion cells (RGCs) in the macaque monkey retina. Their 512-electrode recordings allowed them to sample most, if not all, of the parasol RGCs in a 3-5 mm circle of peripheral retina. To reduce the number of possible input patterns for n cells from ∼2n, the authors applied two constraints. Each input pattern contacts only two cells, establishing pairwise connectivity, and all connected cells must be adjacent. The number of possible patterns was thus reduced to around n2. An analysis of multi-neuron firing patterns indicated that the pairwise and adjacent interactions could account for the experimental results. In principle, this means that by recording from pairs of neighboring cells in a network one can understand the function of the entire circuit (sort of).
4. An Odd Couple: mGluR4 and Medulloblastoma
Luisa Iacovelli, Antonietta Arcella, Giuseppe Battaglia, Simonetta Pazzaglia, Eleonora Aronica, Paola Spinsanti, Alessandra Caruso, Enrico De Smaele, Anna Saran, Alberto Gulino, Mara D'Onofrio, Felice Giangaspero, and Ferdinando Nicoletti
Glutamate receptors don't seem like your everyday target for new anti-cancer drugs. However, biology can be stranger than fiction. In this week's Journal, Iacovelli et al. examined the expression of the group III metabotropic glutamate receptor mGluR4, which is normally expressed on various nerve terminals as well as in cerebellar granule cell precursors. Because the childhood tumor medulloblastoma originates from progenitor cells in the cerebellar external granule layer, the authors looked for mGluR4 expression in the tumor cells. The receptor was expressed in 75% of a sample of medulloblastomas and in several medulloblastoma cell lines. The mGlur4-positive allosteric modulator PHCCC [N-phenyl-7-(hydroxyimino) cyclopropachromen-1a-carboxamide] reduced DNA synthesis and cell proliferation in cell lines and reduced tumor growth in nude mice implanted with medulloblastoma cells. The antigrowth activity of mGluR4 activation appeared to be mediated by inhibition of adenylyl cyclase and decreased activity of the phosphoinositol-3-kinase pathway.