Activation of Group III mGluRs Inhibits GABAergic and Glutamatergic Transmission in the Substantia Nigra Pars Reticulata

2001 ◽  
Vol 85 (5) ◽  
pp. 1960-1968 ◽  
Author(s):  
Marion Wittmann ◽  
Michael J. Marino ◽  
Stefania Risso Bradley ◽  
P. Jeffrey Conn
Keyword(s):  
Substantia Nigra ◽  
Synaptic Transmission ◽  
Globus Pallidus ◽  
Movement Disorders ◽  
Metabotropic Glutamate Receptors ◽  
Substantia Nigra Pars Reticulata ◽  
Projection Neurons ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Primary Output

The GABAergic projection neurons of the substantia nigra pars reticulata (SNr) exert an important influence on the initiation and control of movement. The SNr is a primary output nucleus of the basal ganglia (BG) and is controlled by excitatory inputs from the subthalamic nucleus (STN) and inhibitory inputs from the striatum and globus pallidus. Changes in the output of the SNr are believed to be critically involved in the development of a variety of movement disorders. Anatomical studies reveal that metabotropic glutamate receptors (mGluRs) are highly expressed throughout the BG. Interestingly, mRNA for group III mGluRs are highly expressed in STN, striatum, and globus pallidus, and immunocytochemical studies have shown that the group III mGluR proteins are present in the SNr. Thus it is possible that group III mGluRs play a role in the modulation of synaptic transmission in this nucleus. We performed whole cell patch-clamp recordings from nondopaminergic SNr neurons to investigate the effect of group III mGluR activation on excitatory and inhibitory transmission in the SNr. We report that activation of group III mGluRs by the selective agonist l(+)-2-amino-4-phosphonobutyric acid (l-AP4, 100 μM) decreases inhibitory synaptic transmission in the SNr. Miniature inhibitory postsynaptic currents studies and paired-pulse studies reveal that this effect is mediated by a presynaptic mechanism. Furthermore we found that l-AP4 (500 μM) also reduces excitatory synaptic transmission at the STN-SNr synapse by action on presynaptically localized group III mGluRs. The finding that mGluRs modulate the major inputs to SNr neurons suggests that these receptors may play an important role in motor function and could provide new targets for the development of pharmacological treatments of movement disorders.

Distinct Mechanisms of Presynaptic Inhibition at GABAergic Synapses of the Rat Substantia Nigra Pars Compacta

2005 ◽  
Vol 94 (3) ◽  
pp. 1992-2003 ◽  
Author(s):  
Michela Giustizieri ◽  
Giorgio Bernardi ◽  
Nicola B. Mercuri ◽  
Nicola Berretta
Keyword(s):  
Substantia Nigra ◽  
Presynaptic Inhibition ◽  
Metabotropic Glutamate Receptors ◽  
Calcium Ionophore ◽  
Gaba Release ◽  
Substantia Nigra Pars Compacta ◽  
Gabaergic Neurotransmission ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Voltage Dependent

We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABAB receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist l-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 μM) and the GABAB receptor agonist baclofen (10 μM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 ± 2.7 and 79.3 ± 1.6% (means ± SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 μM) and cadmium (100 μM) were insensitive to AP4 but were reduced by baclofen to 49.7 ± 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 ± 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 ± 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 μM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of α-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 ± 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABAB receptors directly impair transmitter exocytosis.

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