Mark S. Cembrowski

A synaptic mechanism for retinal adaptation to luminance and contrast.

The gain of signaling in primary sensory circuits is matched to the stimulus intensity by the process of adaptation. Retinal neural circuits adapt to visual scene statistics, including the mean (background adaptation) and the temporal variance (contrast adaptation) of the light stimulus. The intrinsic properties of retinal bipolar cells and synapses contribute to background and contrast adaptation, but it is unclear whether both forms of adaptation depend on the same cellular mechanisms. Studies of bipolar cell synapses identified synaptic mechanisms of gain control, but the relevance of these mechanisms to visual processing is uncertain because of the historical focus on fast, phasic transmission rather than the tonic transmission evoked by ambient light. Here, we studied use-dependent regulation of bipolar cell synaptic transmission evoked by small, ongoing modulations of membrane potential (VM) in the physiological range. We made paired whole-cell recordings from rod bipolar (RB) and AII amacrine cells in a mouse retinal slice preparation. Quasi-white noise voltage commands modulated RB VM and evoked EPSCs in the AII. We mimicked changes in background luminance or contrast, respectively, by depolarizing the VM or increasing its variance. A linear systems analysis of synaptic transmission showed that increasing either the mean or the variance of the presynaptic VM reduced gain. Further electrophysiological and computational analyses demonstrated that adaptation to mean potential resulted from both Ca channel inactivation and vesicle depletion, whereas adaptation to variance resulted from vesicle depletion alone. Thus, background and contrast adaptation apparently depend in part on a common synaptic mechanism.

Spatial Gene-Expression Gradients Underlie Prominent Heterogeneity of CA1 Pyramidal Neurons

Tissue and organ function has been conventionally understood in terms of the interactions among discrete and homogeneous cell types. This approach has proven difficult in neuroscience due to the marked diversity across different neuron classes, but it may be further hampered by prominent within-class variability. Here, we considered a well-defined canonical neuronal population—hippocampal CA1 pyramidal cells (CA1 PCs)—and systematically examined the extent and spatial rules of transcriptional heterogeneity. Using next-generation RNA sequencing, we identified striking variability in CA1 PCs, such that the differences within CA1 along the dorsal-ventral axis rivaled differences across distinct pyramidal neuron classes. This variability emerged from a spectrum of continuous gene-expression gradients, producing a transcriptional profile consistent with a multifarious continuum of cells. This work reveals an unexpected amount of variability within a canonical and narrowly defined neuronal population and suggests that continuous, within-class heterogeneity may be an important feature of neural circuits.

Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons

Clarifying gene expression in narrowly defined neuronal populations can provide insight into cellular identity, computation, and functionality. Here, we used next-generation RNA sequencing (RNA-seq) to produce a quantitative, whole genome characterization of gene expression for the major excitatory neuronal classes of the hippocampus; namely, granule cells and mossy cells of the dentate gyrus, and pyramidal cells of areas CA3, CA2, and CA1. Moreover, for the canonical cell classes of the trisynaptic loop, we profiled transcriptomes at both dorsal and ventral poles, producing a cell-class- and region-specific transcriptional description for these populations. This dataset clarifies the transcriptional properties and identities of lesser-known cell classes, and moreover reveals unexpected variation in the trisynaptic loop across the dorsal-ventral axis. We have created a public resource, Hipposeq (http://hipposeq.janelia.org), which provides analysis and visualization of these data and will act as a roadmap relating molecules to cells, circuits, and computation in the hippocampus. DOI: http://dx.doi.org/10.7554/eLife.14997.001

Structured Dendritic Inhibition Supports Branch-Selective Integration in CA1 Pyramidal Cells

Neuronal circuit function is governed by precise patterns of connectivity between specialized groups of neurons. The diversity of GABAergic interneurons is a hallmark of cortical circuits, yet little is known about their targeting to individual postsynaptic dendrites. We examined synaptic connectivity between molecularly defined inhibitory interneurons and CA1 pyramidal cell dendrites using correlative light-electron microscopy and large-volume array tomography. We show that interneurons can be highly selective in their connectivity to specific dendritic branch types and, furthermore, exhibit precisely targeted connectivity to the origin or end of individual branches. Computational simulations indicate that the observed subcellular targeting enables control over the nonlinear integration of synaptic input or the initiation and backpropagation of action potentials in a branch-selective manner. Our results demonstrate that connectivity between interneurons and pyramidal cell dendrites is more precise and spatially segregated than previously appreciated, which may be a critical determinant of how inhibition shapes dendritic computation.

Adaptation to Background Light Enables Contrast Coding at Rod Bipolar Cell Synapses

Rod photoreceptors contribute to vision over an ∼ 6-log-unit range of light intensities. The wide dynamic range of rod vision is thought to depend upon light intensity-dependent switching between two parallel pathways linking rods to ganglion cells: a rod → rod bipolar (RB) cell pathway that operates at dim backgrounds and a rod → cone → cone bipolar cell pathway that operates at brighter backgrounds. We evaluated this conventional model of rod vision by recording rod-mediated light responses from ganglion and AII amacrine cells and by recording RB-mediated synaptic currents from AII amacrine cells in mouse retina. Contrary to the conventional model, we found that the RB pathway functioned at backgrounds sufficient to activate the rod → cone pathway. As background light intensity increased, the RBs role changed from encoding the absorption of single photons to encoding contrast modulations around mean luminance. This transition is explained by the intrinsic dynamics of transmission from RB synapses.

Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina

In many forms of retinal degeneration, photoreceptors die but inner retinal circuits remain intact. In the rd1 mouse, an established model for blinding retinal diseases, spontaneous activity in the coupled network of AII amacrine and ON cone bipolar cells leads to rhythmic bursting of ganglion cells. Since such activity could impair retinal and/or cortical responses to restored photoreceptor function, understanding its nature is important for developing treatments of retinal pathologies. Here we analyzed a compartmental model of the wild-type mouse AII amacrine cell to predict that the cells intrinsic membrane properties, specifically, interacting fast Na and slow, M-type K conductances, would allow its membrane potential to oscillate when light-evoked excitatory synaptic inputs were withdrawn following photoreceptor degeneration. We tested and confirmed this hypothesis experimentally by recording from AIIs in a slice preparation of rd1 retina. Additionally, recordings from ganglion cells in a whole mount preparation of rd1 retina demonstrated that activity in AIIs was propagated unchanged to elicit bursts of action potentials in ganglion cells. We conclude that oscillations are not an emergent property of a degenerated retinal network. Rather, they arise largely from the intrinsic properties of a single retinal interneuron, the AII amacrine cell.

The mechanisms of repetitive spike generation in an axonless retinal interneuron.

Several types of retinal interneurons exhibit spikes but lack axons. One such neuron is the AII amacrine cell, in which spikes recorded at the soma exhibit small amplitudes (<10 mV) and broad time courses (>5 ms). Here, we used electrophysiological recordings and computational analysis to examine the mechanisms underlying this atypical spiking. We found that somatic spikes likely represent large, brief action potential-like events initiated in a single, electrotonically distal dendritic compartment. In this same compartment, spiking undergoes slow modulation, likely by an M-type K conductance. The structural correlate of this compartment is a thin neurite that extends from the primary dendritic tree: local application of TTX to this neurite, or excision of it, eliminates spiking. Thus, the physiology of the axonless AII is much more complex than would be anticipated from morphological descriptions and somatic recordings; in particular, the AII possesses a single dendritic structure that controls its firing pattern.

Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons

Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity. DOI: http://dx.doi.org/10.7554/eLife.06414.001

Single excitatory axons form clustered synapses onto CA1 pyramidal cell dendrites

CA1 pyramidal neurons are a major output of the hippocampus and encode features of experience that constitute episodic memories. Feature-selective firing of these neurons results from the dendritic integration of inputs from multiple brain regions. While it is known that synchronous activation of spatially clustered inputs can contribute to firing through the generation of dendritic spikes, there is no established mechanism for spatiotemporal synaptic clustering. Here we show that single presynaptic axons form multiple, spatially clustered inputs onto the distal, but not proximal, dendrites of CA1 pyramidal neurons. These compound connections exhibit ultrastructural features indicative of strong synapses and occur much more commonly in entorhinal than in thalamic afferents. Computational simulations revealed that compound connections depolarize dendrites in a biophysically efficient manner, owing to their inherent spatiotemporal clustering. Our results suggest that distinct afferent projections use different connectivity motifs that differentially contribute to dendritic integration.Bloss et al. show single axons form clustered inputs onto the dendrites of hippocampal pyramidal cells in a projection-specific manner. The spatial and temporal features inherent in these connections efficiently drive dendritic depolarization.