Positive allosteric modulation of group II mGlu receptor effects on sensory responses in the ventrobasal thalamus in vivo

Caroline Copeland1, Stuart Neale2, Thomas Salt1. 1UCL Institute of Ophthalmology, Visual Neuroscience, London EC1V 9EL, United Kingdom, 2Organon Laboratories, Newhouse ML1 5SH, United Kingdom.

We have previously demonstrated that group II metabotropic glutamate (mGlu) receptors can modulate GABAergic afferent inhibition in the ventrobasal thalamus (VB) (Salt & Turner, 1998; Turner & Salt 2003). Using the broad-spectrum group II (mGlu2 and mGlu3) receptor agonist LY354740 and the mGlu2 receptor sub-type selective positive allosteric modulator (PAM) LY487379, we have investigated whether there is an mGlu2 receptor component to the modulation of sensory responses and GABAergic afferent inhibition in VB.

Using multi-barrel iontophoretic electrodes we made extracellular recordings in vivo from single neurones responsive to somatosensory input in VB of urethane-anaesthetized adult (205-405g) male Wistar rats (n = 34). The effects of LY354740 and LY487379 on sensory responses and responses to NMDA and AMPA applications were assessed. Sensory stimulation was carried out using electronically gated air-jets directed at an individual vibrissa. In order to reveal GABAergic inhibitory processes arising from the thalamic reticular nucleus, we used a condition-test paradigm with two air-jets each directed at an adjacent receptive field area, as detailed previously (Salt, 1989). After control applications of the NMDA/AMPA, or sensory/condition-test paradigms, LY354740 (5mM, pH8.0, in 75mM NaCl) alone, LY487379 (1mM, pH6.0, in 1% DMSO, 75mM NaCl) alone, or the co-application of LY354740 and LY487379 were applied by iontophoresis concurrently with these stimuli. After cessation of LY354740 (12-75nA) and LY487379 (25-100nA) ejection, cycles were continued until responses returned to control levels. Data are expressed as a percentage of control responses prior to LY354740 and/or PAM application (s.e.) and comparisons were made using Wilcoxon matched-pairs test (p < 0.05).

The agonist LY354740 significantly increased responses to short duration (10-30ms) and long duration (500-1000ms) stimuli (126% 5.0, n = 31, and 156% 7.8, n = 21, respectively) when applied alone, and this effect was potentiated when the PAM LY487379 was co-applied (Short: 152% 14.4, n = 19; Long: 215% 24.4, n = 11). LY354740 significantly reduced the inhibition in the condition-test experiments by 21% 3.8 (n = 11) when applied alone, and when the PAM was co-applied this LY354740 effect was potentiated, resulting in a 35% 9.1 (n = 8) reduction in the inhibition. Passage of iontophoretic currents through barrels containing DMSO alone had no significant effect on responses. Responses to AMPA and NMDA were not significantly altered by the application of LY354740 alone (AMPA: 108% 7.3; NMDA: 105% 7.2, n = 23) or LY487379 alone (AMPA: 102% 7.9; NMDA: 102% 3.8, n = 13).

These results are consistent with the finding that group II mGlu receptors have a significant role in the modulation of GABAergic afferent inhibition in VB (Salt & Turner 1998; Turner & Salt 2003). Furthermore, the effectiveness of the mGlu2 receptor PAM indicates a contribution of mGlu2 receptors to the modulation of these responses. This information provides new insight into how mGlu2 selective compounds might work in the brain to modify function of sensory, attentional and cognitive processes.

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