Effects of GABA agonist and antagonist injections into the oculomotor vermis on horizontal saccades

Abstract

The oculomotor vermis (OMV) of the cerebellum is necessary for the generation of the accurate rapid eye movements called saccades. Large lesions of the midline cerebellar cortex involving the OMV cause saccades to become hypometric and more variable. However, saccades were not examined immediately after these lesions so the interpretation of the resulting deficits might have been contaminated by some adaptation to the saccade dysmetria. Therefore, to better understand the contribution of the OMV to normal saccades, we impaired its operation locally by injecting small amounts of either an agonist or antagonist of γ-aminobutyric acid (GABA), which is a ubiquitous neurotransmitter throughout the cerebellar cortex. Muscimol, a GABA agonist, inactivated part of the OMV, whereas bicuculline, an antagonist, disinhibited it. Muscimol caused all ipsiversive horizontal saccades from 5 to 30° to become hypometric. In contrast, bicuculline produced an amplitude-dependent dysmetria: ipsiversive horizontal saccades elicited by target steps <10° became hypometric, whereas those in response to larger steps became hypermetric. At the transition target amplitude, saccade amplitudes were quite variable with some being hypo- and others hypermetric. After most injections of either agent, saccades had lower peak velocities and longer durations than pre-injection saccades of the same amplitude. The longer durations were associated with a prolongation of the deceleration phase. Both agents produced inconsistent effects on contraversive saccades. These results establish that the oculomotor vermis helps control the characteristics of normal ipsiversive saccades and that GABAergic inhibitory processes are a crucial part of this process.

Figure 1

Schematic of the brain stem–cerebellar circuitry involved with leftward saccades. A saccade command from the superior colliculus (SC) reaches excitatory burst neurons (EBN), which drive abducens motoneurons (MN). The SC signal also reaches the oculomotor vermis (OMV) via the nucleus reticularis tegmenti pontis (NRTP). P-cells in OMV inhibit neurons in the caudal fastigial nucleus (cFN). cFN neurons drive inhibitory burst neurons (IBN), which inhibit MNs. Inhibitory interneurons in the OMV (iIN) help shape P-cell activity. Vertical arrows indicate the expected changes in activity that muscimol (filled) or bicuculline (open) injections should produce. Inhibitory neurons are filled; excitatory neurons are open.

Figure 2

Effect of representative muscimol (A,B,C) and bicuculline (D,E,F) injections on saccades to different target step sizes. (A,D) Mean pre- (gray) and post-injection (black) ipsiversive saccade gain at different target step sizes for an exemplar experiment. Error bar: standard deviation. (B,C,E,F) Percent gain change of ipsiversive (B,E) and contraversive (C,F) saccades for all injections. The thick black line and open arrow identify the data in A, D, respectively. Filled circles: significant percent gain changes (p<0.05); open triangles: those that are not (p>0.05).

Figure 3

Effect of muscimol (A,B,C) and bicuculline (D,E,F) injections on ipsiversive saccade main sequence relations. (A,D) Peak velocity versus saccade amplitude for pre- (gray) and post-injection (black) data of an exemplar experiment fit with exponentials. Duration (B,E) and deceleration duration (C,F) versus saccade amplitude with linear fits.

Figure 4

Trajectories of saccades from straight ahead to targets located at an eccentricity of 10° (A) or 20° (B) in 8 equally spaced directions (open squares). (A) Vertical vs. horizontal eye position before and after the muscimol injection illustrated in Fig. 2A. (B) Vertical vs. horizontal eye position before and after the bicuculline injection illustrated in Fig. 2D. All saccades start from their actual initial eye positions.

Figure 5

Time course of the effects of representative muscimol (A) and bicuculline (B) injections on ipsiversive (black) and contraversive (gray) saccade gains. Target steps were 15° in A and 10° in B. Vertical dashed lines indicate the end of the injection. Each point in A and B is the average of 15 and 21 saccades, respectively; bars indicate standard deviations.