Bipolar Cell Pathways in the Vertebrate Retina

Excerpt

Retinal ganglion cells are typically only two synapses distant from retinal photoreceptors, yet ganglion cell responses are far more diverse than those of photoreceptors. The most direct pathway from photoreceptors to ganglion cells is through retinal bipolar cells. Thus, it is of great interest to understand how bipolar cells transform visual signals.

Light response physiology: Werblin and Dowling (1) were among the first to investigate light-evoked responses of retinal bipolar cells. Based on these studies using penetrating microelectrodes, they proposed that retinal bipolar cells lacked impulse activity, and that they processed visual signals through integration of analogue signals, that is synaptic currents and non-spike-generating voltage-gated membrane currents. They also proposed that retinal bipolar cells come in two fundamental varieties: ON-center and OFF-center (Fig. 1). Both types displayed a surround region in their receptive field that opposed the center, similar to the classic, antagonistic center-surround organization earlier described for ganglion-cell receptive fields (2). Ganglion cell receptive field organization is further reviewed in the Webvision chapter on ganglion cells. ON-center bipolar cells are depolarized by small spot stimuli positioned in the receptive field center. OFF-center bipolar cells are hyperpolarized by the same stimuli. Both types are repolarized by light stimulation of the peripheral receptive field outside the center (Fig. 1). Bipolar cells with ON-OFF responses were not encountered (1). ON-OFF responses, excitation at both stimulus onset and offset, first occur among amacrine cells, neurons postsynaptic to bipolar cells.

The Werblin and Dowling characterization of bipolar-cell physiology has proved quite durable over many decades. The notion that bipolar cells do not spike has found exception for some bipolar types. Dark-adapted Mb1 (rod bipolar cells) of goldfish generate light-evoked calcium spikes. These spikes originate in bipolar-cell axon terminals (3, 4). Through genetic imaging techniques this finding has been extended to the axon terminals of many zebrafish bipolar-cell types. In these studies bipolar terminals were labeled transgenically with the Ca²⁺ reporter protein SyGCaMP2 and light-induced fluctuations in Ca²⁺ were followed by 2-photon photometry. Fully 65% of the terminals delivered a spiking Ca²⁺ signal (4). In the cb5b bipolar-cell type of ground squirrel retina Na⁺ action potentials are driven by light. Other bipolar types in this retina do not exhibit spiking (5). These results suggest that bipolar cells are responsible for significantly more of the encoding of visual signals than had been previously supposed, and that axon-terminal spiking is actively involved. Impulse generation in bipolar cells is further discussed in the section on Voltage-gated currents.

Morphology and connectivity: Anatomical investigations of bipolar cells reveal a multiplicity (4-22 depending on species) of different morphological types (6-12), significantly more than the just two types that early physiology implied. The diversity of human retinal bipolar types is illustrated in Fig. 2. Nonetheless all of these are either ON- or OFF-types and their diversity results from other factors, such as differing connectivity with photoreceptors and differing postsynaptic targets, as evidenced in the diversity of dendritic and axon-terminal ramification patterns. Some bipolar cells are postsynaptic only to rods, others only to cones (Fig. 2), and still others receive mixed rod-cone input. Among cone-selective bipolar cells, some innervate only red, green, or blue cones, while others are ‘diffuse’, that is, not selective (13-19). Different bipolar types express different glutamate receptors at subsynaptic contacts with cones.

Bipolar cell axon terminals are either mono- or multistratified, depending on the location of axonal boutons and branches in the inner plexiform layer (IPL). Differing terminal position and branching morphology within the IPL suggests that different morphological types selectively innervate different types of amacrine and ganglion cell (Fig 2). In primate retinas, bipolar cells are described as diffuse or midget types, based on the extent of the dendritic arbor. Midgets contact only a single cone, while diffuse types contact multiple cones. Bipolar cells are also termed ‘flat’ or ‘invaginating’ (20) depending on the placement of dendritic tips, either on the surface of (flat), or penetrating within photoreceptor synaptic terminals to approach presynaptic ribbons (invaginating). Fig. 2 illustrates 11 morphological types of bipolar cell seen in Golgi-stained human retinas.