Isoniazid-induced reduction in GABAergic neurotransmission alters the function of the cerebellar cortical circuit.
The cerebellar cortex contributes to the control of movement, coordination, and certain cognitive functions. The cerebellar network is composed of five different types of neurons that are wired together in a repetitive module. Given that four of these five neurons synthesize and release GABA, this inhibitory neurotransmitter plays a central role in regulation of the excitability and correct functioning of the cerebellar cortex. We have now used isoniazid, an inhibitor of glutamic acid decarboxylase, the enzyme responsible for the synthesis of GABA, to evaluate the contribution of GABAergic transmission in different types of cerebellar cortical neurons to the functioning of the cerebellar circuit. Parasagittal cerebellar slices were prepared from 28- to 40-day-old male rats and were subjected to patch-clamp recording in the voltage- or current-clamp mode. Exposure of the tissue slices to isoniazid (10 mM) resulted in a decrease in the level of GABAergic transmission in Purkinje cells and a consequent increase in the firing rate of spontaneous action potentials that was apparent after 40 min. In granule neurons, isoniazid reduced both tonic and phasic GABAergic currents and thereby altered the flow of information across the cerebellar cortex. Our data support the notion that the amount of GABA at the synaptic level is a major determinant of the excitability of the cerebellar cortex, and they suggest that isoniazid may be a useful tool with which to study the function of the cerebellar network.
Carta
M
M
Department of Experimental Biology Bernardo Loddo, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, SS 554, Km 4,500, Monserrato CA, Italy. mcarta@unica.it
Murru
L
L
Barabino
E
E
Talani
G
G
Sanna
E
E
Biggio
G
G
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002525:Cerebellar Cortex / Q000187:drug effects*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D009415:Nerve Net / Q000187:drug effects*; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D007538:Isoniazid