The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Abstract

The main glutamate transporter GLT-1 is responsible for clearing synaptically released glutamate from the extracellular space and contributes to the shaping of glutamatergic transmission. Recently, it has been shown that ceftriaxone (CEF)-induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a simple form of information processing that is reduced in schizophrenia, and determines a strong reduction in hippocampal metabotropic glutamate receptor (mGluR)2/3-dependent long-term depression. In this study, we tested the hypothesis that administration of the mGluR2/3 agonist LY379268 blocks the effect of GLT-1 upregulation on PPI of the startle. We showed that administration of LY379268 (1 mg/kg) prevented PPI alterations associated with GLT-1 upregulation, suggesting that CEF-induced PPI impairment was mGluR2/3 dependent. In addition, we showed that CEF-induced GLT-1 upregulaton did not alter the expression of mGluR2/3, and also that it occurred at sites of mGluR2/3 expression. These results indicate a novel mechanism by which GLT-1 upregulation modulates PPI of the startle.

Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine

“…Interestingly, the reduced locomotor response to AMP by the group 1 mGluR antagonist was blocked by infusion of a group 2 mGluR agonist. Group 2 mGluRs negatively regulate glutamate release (Baker et al, 2002) and have also been shown to be in close proximity to GLT-1 (Bellesi and Conti, 2010). Based on such findings, we predicted that the defect in glutamate homeostasis produced by deletion of GLT-1 in neurons, which would presumably increase local extracellular glutamate levels, might diminish the behavioral effects of AMP, conceivably via increased activation of group 2 mGluRs.…”

Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats

“…Wan and Swerdlow 1996). Pharmacological upregulation of Slc1a2 potently disrupts PPI in SD rats, an effect that appears to be dependent on reduced glutamate activity at metabotropic [(mGluR)2/3] glutamate receptors (Bellesi et al 2009; Bellesi and Conti 2010). In those studies, PPI levels were found to correlate strongly (r=−0.67) with SLC1A2 levels in frontal cortex (Bellesi et al 2009), an effect that was not detected in the present study, in either sham or NVHL group rats.…”

The Effects of Acupuncture on Glutamatergic Neurotransmission in Depression, Anxiety, Schizophrenia, and Alzheimer's Disease: A Review of the Literature

“…A broad-spectrum cephalosporin antibiotic, ceftriaxone stimulates EAAT2 expression and lessens neurotoxicity by inhibiting neuronal cell death associated with glutamate excitotoxicity (68). Upregulation of EAAT2 expression by ceftriaxone is thought to be via presynaptic activation of the mGluR, as mGluR2/3 agonist treatment prevented the PPI impairment associated with ceftriaxone-induced upregulation of EAAT2 in rats (69). EAAT2 overexpression causing PPI impairment may be due to glutamate spillover, which mGluR2/3 relies on for activation due to its perisynaptic localization (54).…”