Visual information is processed in the retina to a remarkable degree before it is transmitted to higher visual centres. Several types of retinal ganglion cells (the output neurons of the retina) respond preferentially to image motion in a particular direction, and each type of direction-selective ganglion cell (DSGC) is comprised of multiple subtypes with different preferred directions. The direction selectivity of the cells is generated by diverse mechanisms operating within microcircuits that rely on independent neuronal processing in individual dendrites of both the DSGCs and the presynaptic neurons that innervate them.
There are two subclasses of alpha cell in the mammalian retina, which are morphologically identical in plain view but have opposite responses to a luminance change: one is ON center and the other is OFF center. Recent studies have shown that the neural circuitries, which underlie light responses in such ON-and OFF-ganglion cell pairs, are not mirror symmetric with respect to the ON and OFF pathways (Pang et al., 2003;Zaghloul et al., 2003;Murphy & Rieke, 2006). This study examines alpha-cell homologues in the mouse retina and elucidates the synaptic mechanisms that generate their light responses. Morphological analysis of recorded cells revealed three subclasses that were essentially identical in plan view but had distinct vertical stratification levels. We refer to these cells as the sustained ON (ON-S), sustained OFF (OFF-S), and transient OFF (OFF-T) cells (Murphy & Rieke, 2006;Margolis & Detwiler, 2007). Both ON-S and OFF-S cells were largely driven through the ON pathway via changes in excitatory and inhibitory inputs, respectively. Light responses of OFF-T cells were driven by transient changes in excitatory and inhibitory inputs. Light responses of OFF-S cells were also measured in connexin 36 knockout mice in order to dissect glycinergic input arising from AII amacrine cells. At photopic/mesopic intensities, peak glycinergic input to OFF-S cells in the connexin 36 knockout mouse was reduced by ~85% compared to OFF-S cells in the wildtype retina. This is consistent with the idea that AII cells receive their input from ON-cone bipolar cells through gap junctions and in turn provide glycinergic inhibition to OFF-S cells.
The synaptic conductance of the On-Off direction-selective ganglion cells was measured during visual stimulation to determine whether the direction selectivity is a property of the circuitry presynaptic to the ganglion cells or is generated by postsynaptic interaction of excitatory and inhibitory inputs. Three synaptic asymmetries were identified that contribute to the generation of direction-selective responses: (1) a presynaptic mechanism producing stronger excitation in the preferred direction, (2) a presynaptic mechanism producing stronger inhibition in the opposite direction, and (3) postsynaptic interaction of excitation with spatially offset inhibition. Although the on-and off-responses showed the same directional tuning, the off-response was generated by all three mechanisms, whereas the on-response was generated primarily by the two presynaptic mechanisms. The results indicate that, within a single neuron, different strategies are used within distinct dendritic arbors to accomplish the same neural computation.Key words: direction selectivity; ganglion cells; synaptic conductance; inhibition; excitation; dendritic integration; on-and off-pathways; rabbit retinaThe direction-selective ganglion cells (DSGCs) in the rabbit retina are a model system for investigating neural computation (Vaney et al., 2001). These cells respond strongly to an image moving in a preferred direction but only weakly to an image moving in the opposite "null" direction. The foundation for understanding the cellular mechanisms of direction selectivity in vertebrates was laid by Barlow and Levick (1965), whose extracellular recordings from DSGCs indicated that direction selectivity was mediated primarily by inhibition activated by nulldirection image motion. Strong support for the inhibitory model was provided by subsequent pharmacological experiments, which showed that GABA A -receptor antagonists abolish direction selectivity (Wyatt and Daw, 1976;Ariel and Daw, 1982;Kittila and Massey, 1997). However, these extracellular recording experiments provided no information about whether the inhibition acted directly on the DSGC or presynaptically on the excitatory interneurons.Torre and Poggio (1978) proposed a postsynaptic model in which DSGCs receive an inhibitory input that is spatially offset relative to the excitatory input; moreover, the inhibition is nondirectional, being activated equally well by image motion in the preferred and null directions. During null-direction motion, the spatial offset means that delayed inhibitory synapses at locations ahead of the stimulus are activated and veto the excitation as the stimulus sweeps across the receptive field. For preferreddirection motion, the inhibition trails behind the stimulus and thus arrives too late to veto the excitation. For this model to work, the inhibition must act locally within the dendritic arbor of the DSGC. This occurs when the inhibitory reversal potential is at, or close to, the resting potential of the cell, and therefore the inhibitory input does not polarize the c...
Dendritic spikes that propagate toward the soma are well documented, but their physiological role remains uncertain. Our in vitro patch-clamp recordings and two-photon calcium imaging show that direction-selective retinal ganglion cells (DSGCs) utilize orthograde dendritic spikes during physiological activity. DSGCs signal the direction of image motion. Excitatory subthreshold postsynaptic potentials are observed in DSGCs for motion in all directions and provide a weakly tuned directional signal. However, spikes are generated over only a narrow range of motion angles, indicating that spike generation greatly enhances directional tuning. Our results indicate that spikes are initiated at multiple sites within the dendritic arbors of DSGCs and that each dendritic spike initiates a somatic spike. We propose that dendritic spike failure, produced by local inhibitory inputs, might be a critical factor that enhances directional tuning of somatic spikes.
SUMMARY1. Cells in the ganglion cell layer of salamander retinal slices were voltage clamped using patch pipettes. Light elicited transient excitatory postsynaptic currents (EPSCs) in on-off ganglion cells and sustained EPSCs in on ganglion cells. Lightevoked inhibitory postsynaptic currents in these cells could be blocked by 100 /LMbicuculline methobromide and 500 nM-strychnine.2. In the presence of external Cd2", at a concentration that blocked light-evoked synaptic inputs, NV-methyl-D-aspartate (NMDA) and the non-NMDA-receptor agonists, quisqualate and kainate, gated conductances in both on-off and on ganglion cells. The current-voltage (I-V) curve for the conductance elicited by NMDA had a negative slope between -40 and -70 mV and a reversal potential near 0 mV. The I-V curves for the non-NMDA-receptor-mediated conductances were nearly linear and also had reversal potentials near 0 mV.3. I-V curves were measured at an early time point near the peak of transient EPSCs and at a later time point during the decay phase of the responses. The late I-V curve had a negative slope below -40 mV. The early I-V curve had a positive slope over the entire voltage range but the slope was greater at positive than at negative potentials. The evoked current reversed near 0 mV at both time points.4. The region of negative slope of the late I-V curve was eliminated when Mg2" was removed from the external saline. A slowly decaying component of transient EPSCs was eliminated in 20 /tM-DL-2-amino-7-phosphonoheptanoate (AP7), an NMDAreceptor antagonist.5. Application of 1 /aM-6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA-receptor antagonist at this concentration, blocked a fast component of transient EPSCs.6 S. MITTMAN, W. R. TA YLOR AND D. R. COPENHAGEN n = 5), and a faster non-NMDA-receptor-mediated component having a time-topeak of 28 + 10 ms and an e-fold decay time of 43 + 20 ms at -31 mV (n = 8).7. A similar analysis of sustained EPSCs of on ganglion cells showed that these currents resulted from sustained activation of both NMDA and non-NMDA receptors.
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