Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Abstract

Deficiencies in N‐methyl‐d‐aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc− (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual‐probe microdialysis with ultra‐high‐pressure liquid chromatography. Effects of MK801 and MEM on Sxc activity were also determined using primary cultured astrocytes. Sxc activity was enhanced by MEM, but was unaffected by MK801. MK801 enhanced thalamocortical glutamatergic transmission by GABAergic disinhibition in the MDTN. In the MDTN and the mPFC, MEM weakly increased glutamate release by activating Sxc, whereas MEM inhibited thalamocortical glutamatergic transmission. Paradoxical effects of MEM were induced following secondary activation of inhibitory II‐mGluR and III‐mGluR by exporting glutamate from astroglial Sxc. The present results suggest that the effects of therapeutically relevant concentrations of MEM on thalamocortical glutamatergic transmission are predominantly caused by activation of Sxc rather than inhibition of NMDAR. These demonstrations suggest that the combination between reduced NMDAR and activated Sxc contribute to the neuroprotective effects of MEM. Furthermore, activation of Sxc may compensate for the cognitive impairments that are induced by hyperactivation of thalamocortical glutamatergic transmission following activation of Sxc/II‐mGluR in the MDTN and Sxc/II‐mGluR/III‐mGluR in the mPFC.

Lurasidone inhibits NMDA receptor antagonist‐induced functional abnormality of thalamocortical glutamatergic transmission via 5‐HT7 receptor blockade

“…Based on the established thalamocortical and related networks, the present study was designed. The MDTN is strongly regulated by GABAergic inhibition from the RTN (Asanuma, ) and the MDTN (Fukuyama et al, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ). The pyramidal neurons in the frontal cortex receive at least three projections from the LC and VTA.…”

“…The pyramidal neurons in the frontal cortex receive at least three projections from the LC and VTA. Both selective noradrenergic terminals from the LC and selective dopaminergic terminals from the VTA project to deeper layers of the frontal cortex, whereas co‐releasing catecholaminergic terminals (noradrenaline and dopamine) from the LC project to the superficial layers of the frontal cortex (Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ; Yamamura, Ohoyama, Hamaguchi, Kashimoto, et al, ; Yamamura, Ohoyama, Hamaguchi, Nakagawa, et al, ). In the deeper layers, the presynaptic terminals of selective noradrenergic and dopaminergic projections are regulated by inhibitory GABAergic input, whereas in the superficial layers, the co‐releasing catecholaminergic presynaptic terminals are regulated by the excitatory thalamocortical glutamatergic pathway via activation of AMPA receptors (Ohoyama et al, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ; Yamamura, Ohoyama, Hamaguchi, Kashimoto, et al, ; Yamamura, Ohoyama, Hamaguchi, Nakagawa, et al, ).…”

“…To accurately measure the concentrations of lurasidone and MK‐801 in the insula, MDTN, and RTN, in vivo probe diffusion was determined according to a reverse dialysis procedure (Okada, Fukuyama, Kawano, Shiroyama, Suzuki, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ; Okada, Yoshida, Zhu, Hirose, & Kaneko, ). Solute diffusion occurs in both directions across dialysis membranes; hence, the loss of solute from the perfusate occurs at the same rate as recovery of the solute into the perfusate.…”

“…The frontal cortex receives two major glutamatergic projections: one from other cortical regions and one from the mediodorsal thalamic nucleus (MDTN) (Kuroda, Yokofujita, & Murakami, ; Yamamura, Ohoyama, Hamaguchi, Kashimoto, et al, ; Yamamura, Ohoyama, Hamaguchi, Nakagawa, et al, ). Recently, we demonstrated that aripiprazole, memantine and guanfacine, all of which improve cognitive function, normalized thalamocortical glutamatergic abnormalities in the mPFC and orbitofrontal cortex (Fukuyama et al, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ).…”

“…Systemic administration of NMDA receptor antagonists also increased l ‐glutamate release in the mPFC (Fukuyama, Hasegawa, & Okada, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ), resulting in increased firing of cortical neurons (Lorrain, Baccei, Bristow, Anderson, & Varney, ). In contrast to systemic administration, however, local infusion of an NMDA receptor antagonist directly into the mPFC did not affect regional extracellular l ‐glutamate levels (Tanahashi, Yamamura, Nakagawa, Motomura, & Okada, ; Yamamura, Ohoyama, Hamaguchi, Kashimoto, et al, ; Yamamura, Ohoyama, Hamaguchi, Nakagawa, et al, ).…”