Abstract
Group II metabotropic glutamate receptor (mGluR) ligands are potential novel drugs for neurological and psychiatric disorders, but little is known about the effects of these compounds at synapses of the human cerebral cortex. Investigating the effects of neuropsychiatric drugs in human brain tissue with preserved synaptic circuits might accelerate the development of more potent and selective pharmacological treatments. We have studied the effects of group II mGluR activation on excitatory synaptic transmission recorded from pyramidal neurons of cortical layers 2–3 in acute slices derived from surgically removed cortical tissue of people with epilepsy or tumors. The application of a selective group II mGluR agonist, LY354740 (0.1–1 μM) inhibited the amplitude and frequency of action potential-dependent spontaneous excitatory postsynaptic currents (sEPSCs). This effect was prevented by the application of a group II/III mGluR antagonist, CPPG (0.1 mM). Furthermore, LY354740 inhibited the frequency, but not the amplitude, of action potential-independent miniature EPSCs (mEPSCs) recorded in pyramidal neurons. Finally, LY354740 did slightly reduce cells’ input resistance without altering the holding current of the neurons recorded in voltage clamp at -90 mV. Our results suggest that group II mGluRs are mainly auto-receptors that inhibit the release of glutamate onto pyramidal neurons in layers 2–3 in the human cerebral cortex, thereby regulating network excitability. We have demonstrated the effect of a group II mGluR ligand at human cortical synapses, revealing mechanisms by which these drugs could exert pro-cognitive effects and treat human neuropsychiatric disorders.
Highlights
Pre- and postsynaptic metabotropic glutamate receptors are activated by L-glutamate, the major excitatory transmitter in the mammalian central nervous system (CNS)
All neurons included in this study displayed membrane responses, action potential kinetics and discharge patterns consistent with features commonly observed in human cortical pyramidal neurons in layers 2–3 (Molnár et al, 2008) (Table 2 and Figure 1)
MEPSC amplitude was not significantly altered by LY354740. These results suggest that activation of group II metabotropic glutamate receptor (mGluR) leads to presynaptic and postsynaptic effects in pyramidal cells
Summary
Pre- and postsynaptic metabotropic glutamate receptors (mGluRs) are activated by L-glutamate, the major excitatory transmitter in the mammalian central nervous system (CNS). Group II receptors (mGlu and mGlu3) are intriguing due to their peri- and extra-synaptic location outside the synaptic junction (Shigemoto et al, 1997; Corti et al, 2002), predicting receptor activation in an activity-dependent manner when glutamate spills over from the release site (Scanziani et al, 1997). This process may be of interest under physiological and under pathological conditions (Molinari et al, 2012). Group II mGluRs are often coupled to the cyclic AMP cascade (Conn and Pin, 1997) and are potently activated by a series of compounds developed by several pharmaceutical companies and by Eli Lilly and Company, for example (1)-2aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740) (Schoepp et al, 1999)
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