IOP regulation in the suprachiasmatic nucleus through glutamatergic and GABAergic neuronal pathways

Abstract

Purpose : Glaucoma is a leading cause of blindness in adults despite a variety of management strategies which help to slow its progression. In a quest to identify a new pharmacological approach for regulating intraocular pressure (IOP), a primary cause of glaucoma, this research focuses on the brain center that modulates most circadian rhythms, which potentially includes IOP variation. Our objective was to chemically stimulate the SCN directly by microinjection of either a glutamate receptor agonist, NMDA, or the GABA_A receptor antagonist, BMI, and determine the role of these two major signaling systems in the regulation of IOP within the SCN.

Methods : Male Sprague-Dawley rats (n=38) were placed under mild isoflurane anesthesia at midday. Using a stereotactic surgical approach, a 75 nL injectate of 0.4 mM BMI, or a dose range of NMDA 13-51 mM, or control 0.1M phosphate buffered saline, was delivered to the targeted area of the anterior hypothalamus after 10 minutes of stable baseline recordings of IOP, heart rate (HR), blood pressure (MAP), and intracranial pressure (ICP) were obtained. IOP, ICP and the cardiac responses were monitored for 60 minutes following injection.

Results : When injected directly into the SCN of anesthetized rats, both BMI (n=5) and saline (n=5) produced a rise in IOP (Fig. 1) that was 2.6 to 3.9-fold greater, respectively, than the NMDA response (n=5), which was near background level (saline-NMDA difference = 9.8 mm Hg, 3.9 fold +/- 1.5, n=10, AUC p=0.001; BMI-NMDA difference = 3.8 +/- 2.4 mm Hg, 2.7 fold +/- 1.5, n=10, AUC p=0.03). Alternatively, saline injected into either the ventricle (n=2) or the optic chiasma/supraoptic decussate region (och/sod) (n=5) did not stimulate a rise in IOP. BMI injected into the ventricle (n=3), however, led to a significant rise in IOP (3.6 +/- 1.0-fold relative to saline, p=0.03). Neither saline, BMI, nor NMDA injection into the SCN led to a significant rise in HR or MAP. ICP, however, was significantly increased by BMI microinjection into the SCN (3.1-fold rise relative to the saline response (p=0.03, n=9).

Conclusions : These data support the hypothesis that CNS regulation of IOP can be independent from HR, MAP, and ICP modulation, and suggest that IOP may be regulated through the SCN by both glutamatergic and GABAergic neuronal pathways.

This is a 2021 ARVO Annual Meeting abstract.

 

Fig.1: IOP responses following SCN injection at time=0 (smoothed curves with 95% confidence intervals)