Nathan R. Wilson

Regulation of dendritic spine morphology and synaptic function by Shank and Homer.

The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction.

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Response features of parvalbumin-expressing interneurons suggest precise roles for subtypes of inhibition in visual cortex.

Inhibitory interneurons in the cerebral cortex include a vast array of subtypes, varying in their molecular signatures, electrophysiological properties, and connectivity patterns. This diversity suggests that individual inhibitory classes have unique roles in cortical circuits; however, their characterization to date has been limited to broad classifications including many subtypes. We used the Cre/LoxP system, specifically labeling parvalbumin(PV)-expressing interneurons in visual cortex of PV-Cre mice with red fluorescent protein (RFP), followed by targeted loose-patch recordings and two-photon imaging of calcium responses in vivo to characterize the visual receptive field properties of these cells. Despite their relative molecular and morphological homogeneity, we find that PV+ neurons have a diversity of feature-specific visual responses that include sharp orientation and direction-selectivity, small receptive fields, and band-pass spatial frequency tuning. These results suggest that subsets of parvalbumin interneurons are components of specific cortical networks and that perisomatic inhibition contributes to the generation of precise response properties.

Synaptic reorganization in scaled networks of controlled size.

Neurons in plastic regions of the brain undergo fundamental changes in the number of cells connecting to them as a result of development, plasticity and disease. Across these same time periods, functional changes in cellular and synaptic physiology are known to occur and are often characterized as developmental features of these periods. However, it remains possible that many such changes are direct consequences of the modified degree of partnering, and that neurons intrinsically scale their physiological parameters with network size. To systematically vary a recurrent networks number of neurons while measuring its synaptic properties, we used microfabricated extracellular matrix adhesive islands created with soft lithography to culture neuronal clusters of precise sizes, and assessed their intrinsic connectivity using intracellular recordings and confocal microscopy. Both large and small clusters supported constant densities of excitatory and inhibitory neurons. However, neurons that were provided with more potential partners (larger clusters) formed more connections per cell via an expanded dendritic surface than cocultured smaller clusters. Electrophysiologically, firing rate was preserved across clusters even as size and synapse number increased, due in part to synapses in larger networks having reduced unitary strengths, and sparser paired connectivity. Larger networks also featured a particular increase in the number of excitatory connections onto inhibitory dendrites. We suggest that these specific homeostatic mechanisms, which match the number, strength, and architecture of connections to the number of total available cellular partners in the network, could account for several known phenomena implicated in the formation, organization and degeneration of neuronal circuits.

El-Boustani et al. reply

replying to S.-H. Lee, A. C. Kwan & Y. Dan 508, http://dx.doi.org/10.1038/nature13128 (2014)Several recent studies have examined the function of parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) inhibitory neurons in V1 (refs 1, 2, 3). Although it is commonly agreed that these cell types alter the responses of pyramidal neurons in distinct ways—via divisive or subtractive inhibition—their specific roles remain a matter of debate. The Comment by Lee et al. presents new data suggesting that the differences between the results of Lee et al. compared to Atallah et al. and Wilson et al. could be explained by the strength and duration of laser stimulation used to optogenetically activate these two classes of inhibitory neuron. The data presented by Lee et al. now clarify that PV+ neurons, when probed with small amounts of optogenetic activation, do not significantly change the tuning of their target cells, confirming Atallah et al. and Wilson et al.. The new SST+ results presented in the Comment show that SST+ neurons can subtract responses, consistent with Wilson et al., but we suggest that the switch of function of SST+ neurons in their data between short (1 s) and long (4–5 s) stimulation reveals a core principle of inhibition in cortical networks rather than simply being a peculiarity of stimulation protocols. The fundamental difference between these two conditions resides in the temporal overlap between inhibitory neuron activation and target-cell responses: when these overlap, inhibition is divisive (causing no change in tuning width of target neurons), but when they do not overlap, inhibition is subtractive (and reduces tuning width).