Neal and Cunningham (Neal, M. J., and J. R. Cunningham. 1995. J. Physiol. (Lond.). 482:363-372) showed that GABA^sub B^ agonists and glycinergic antagonists enhance the light-evoked release of retinal acetylcholine. They proposed that glycinergic cells inhibit the cholinergic Starburst amacrine cells and are in turn inhibited by GABA through GABA^sub B^ receptors. However, as recently shown, glycinergic cells do not appear to have GABA^sub B^ receptors. In contrast, the Starburst amacrine cell has GABA^sub B^ receptors in a subpopulation of its varicosities. We thus propose an alternate model in which GABA^sub B^-receptor activation reduces the release of ACh from some dendritic compartments onto a glycinergic cell, which then feeds back and inhibits the Starburst cell. In this model, the GABA necessary to make these receptors active comes from the Starburst cell itself, making them autoreceptors. Computer simulations of this model show that it accounts quantitatively for the Neal and Cunningham data. We also argue that GABA^sub B^ receptors could work to increase the sensitivity to motion over other stimuli.

One of the most important unanswered questions in retinal neurohiology is why the Starhurst eholinergic amacrine cells have two neurotransmitters (1-4). These cells produce both acctylcholinc (ACh) and γ-aminohutyric acid (GABA), releasing them upon light stimulation (5-9). The released ACh has many roles in the retina, including the enhancement of motion sensitivity (10-12) and the establishment of directional selectivity for some types of stimuli (13-20). In turn, recent evidence shows that GABA is the main transmitter involved in directional selectivity (6,7,21). In this article, we discuss another possible role suggested by the eholinergic amacrine cells themselves containing GABA^sub B^ receptors (22). Because these receptors often work as autoreceptors in the brain (23-25), this raises the possibility that GABA from these cells feeds back onto them to control their release of ACh. This control could he by hyperpolarization (26,27), by reducing a Ca^sup 2+^-dependent current (28-30) through a G-protein mechanism (30-32), or by facilitating a L-type Ca^sup 2+^ channel (33). The results of Neal and Cunningham (5) coupled to the results of Zucker et al. (22) lend some support to such an autorcceptor control (see also (34)). Neal and Cunningham showed that the GABA^sub B^ agonist baclofen and the glycinergic antagonist strychnine enhance the light-evoked release of retinal ACh. Considering these results, they proposed that glycinergic cells inhibit the Starburst cells and are in turn inhibited by GABA through GABA^sub B^ receptors. However, as shown by Zucker et al. (22), glycinergic cells do not appear to have GABA^sub B^ receptors. Consequently, one must search an alternate hypothesis for the role of these receptors. The simplest alternative given the available data is that GABA^sub B^ agonists enhance the release of ACh by acting on the Starburst cells themselves. These cells may synapse onto glyeinergic cells (which probably include the cholinoreceptive DAPI-3 cell (22,35,36) through muscarinic receptors. (The receptors may be chemically ephaptic, that is, ACh may diffuse to targets far from the presynaptic site; this would help to explain the apparent dearth of conventional synapses made by Starburst cells onto noncholinergic amacrine cells (37)). In addition, retinal cholinergic receptors are often far away from the site of cholinergic release (38)-the glyeinergic cells of ACh may provide contact back onto Starbursl cells (5.39). Hence, the activation of GABA^sub B^ receptors may result in disinhibition.

In this article, we use a biophysical model to test the feasibility of the GABA^sub B^-auloreceptor hypothesis for Starburst cells. To know whether this hypothesis will work is not so easy. One difficulty is to know how GABA^sub B^ agonists reduce the muscarinic input to the glyeinergic cell at the same time that they increase the overall release of ACh. Perhaps the answer lies in the recent surprising finding that only ~257(of Starburst-cell varicosities contain GABA^sub B^ receptors (22). If the input to glyeinergic cells came only from these varicosities. then GABA^sub B^ agonists might affect these cells without reducing ACh release from other varicosities. However, the model must solve another problem with GABAergic action on Starburst cells. The release of ACh from Starburst cells may be also inhibited by GABA through GABA^sub A^ receptors (8,16,39,40). How is it that the GABA that putatively feeds back to the GABA^sub B^ autoreceptordoes not inhibit the ACh release through the GABA^sub A^ hcteroreceptor? The model provides answers to these questions and lits the Neal and Cunningham data well. An abstract version of the model appeared elsewhere (41).

The next section of this article will provide the model assumptions and their justifications, along with a physical description of the model. That section will include no equations to facilitate the comprehension of the ideas. The model equations and the parameters used in the simulations will appear in Appendices A and B, respectively.