Presynaptic Inhibition Modulates Spillover, Creating Distinct Dynamic Response Ranges of Sensory Output

Abstract

Sensory information is thought to be modulated by presynaptic inhibition. Although this form of inhibition is a well-studied phenomenon, it is still unclear what role it plays in shaping sensory signals in intact circuits. By visually stimulating the retinas of transgenic mice lacking GABAc receptor-mediated presynaptic inhibition, we found that this inhibition regulated the dynamic range of ganglion cell (GC) output to the brain. Presynaptic inhibition acted differentially upon two major retinal pathways; its elimination affected GC responses to increments, but not decrements, in light intensity across the visual scene. The GC dynamic response ranges were different because presynaptic inhibition limited glutamate release from ON, but not OFF, bipolar cells, which modulate the extent of glutamate spillover and activation of perisynaptic NMDA receptors at ON GCs. Our results establish a role for presynaptic inhibitory control of spillover in determining sensory output in the CNS.

Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input

“…The distinctive rhythmic voltage fluctuations and spike activity present in the RD retina is not present in these cell types in WT retina (Pang et al, 2003;Murphy and Rieke, 2006;Sagdullaev et al, 2006;Margolis and Detwiler, 2007). Nor has this activity been reported under physiological conditions in any other type of adult mammalian RGC.…”

“…These ages represent later stages in the degenerative disease and show evidence of more advanced changes in retina structures Marc et al, , 2007. In this, as in other studies (Pang et al, 2003;Murphy and Rieke, 2006;Sagdullaev et al, 2006;Margolis and Detwiler, 2007), information about WT (C57BL/6) RGCs was obtained from adult (P28 -P56) animals and used for controls as indicated in the figures. Both WT and RD mice were obtained from The Jackson Laboratory.…”

“…In normal (WT) RGCs, the resting spike activity in the absence of light is irregular with little underlying temporal structure (Pang et al, 2003;Murphy and Rieke, 2006;Sagdullaev et al, 2006;Margolis and Detwiler, 2007). In contrast, in RD mice, ON, OFF-T, and OFF-S RGCs displayed striking and consistent patterns of rhythmic resting spike activity (Fig.…”

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

“…Plotting the average peak amplitude of events measured in five cells (one ON, three OFF, and one ON-OFF) against the holding potential revealed a nonlinear relationship characteristic of events mediated by a combination of AMPA/KA and NMDA receptors (Fig. 2C) (Diamond and Copenhagen, 1993;Sagdullaev et al, 2006;Manookin et al, 2010). Indeed, these events were largely suppressed by NBQX and AP-5 (89 Ϯ 6% block; n ϭ 3), which are selective antagonists for AMPA/ kainate (KA) and NMDA receptors, respectively.…”

“…L-AP-4 might also act on axonal terminals of bipolar cells (Awatramani and Slaughter, 2001) and amacrine cells (Quraishi et al, 2007); therefore, these data need to be interpreted with caution. To monitor activity in ganglion cells in the presence of NBQX, in these experiments, we took advantage of the selective expression of synaptic NMDA receptors in these cells (Diamond and Copenhagen, 1993;Sagdullaev et al, 2006;Manookin et al, 2010) and monitored output of bipolar cells as NMDA-receptor-mediated sEPSCs at a holding potential of ϩ40 mV (in which these receptors would be relieved of their Mg 2ϩ block) (Jahr and Stevens, 1990). Using this method, the intrinsic activity of the cone bipolar/AII amacrine cell network was assessed in relative isolation.…”