PATTERNS OF EXCITATORY AND INHIBITORY SYNAPTIC TRANSMISSION IN THE RAT NEOSTRIATUM AS REVEALED BY 4-AP

1. Synaptic potentials induced by 4-aminopyridine (4-AP) were recorded intracellularly from rat neostriatal neurons in an in vitro slice preparation. EC(50) for this 4-AP action was similar to 120 mu M. The threshold for activation of synaptic potentials was 5 mu M. 2. 4-AP-induced synaptic potentials appeared stochastically. Most were blocked by 1 mu M tetrodotoxin or 400 mu M Cd2+. Therefore they reflect a release of neurotransmitters dependent on both Ca2+ entry to the terminals and action potential firing. 3. Bicuculline (BIG) (less than or equal to 10 mu M), a gamma-aminobuturic acid-A (GABA(A)) antagonist, blocked about half of the 4-AP-induced synaptic potentials. This suggests that intrinsic inhibitory connections within the neostriatum are activated by 4-AP administration. 4. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; less than or equal to 10 mu M) plus D-2-amino-5-phosphonovaleric acid (D-APV; less than or equal to 100 mu M) blocked most of the BIG-resistant 4-AP-induced synaptic potentials. This suggests that 4-AP induced release of glutamate (GLU) from extrinsic glutamatergic afferents. As most glutamatergic afferents are extrinsic, these afferents then would be able to fire spikes and release transmitter for several hours after they are cut from their somata. 5. If CNQX plus D-APV were administered before BIG, neostriatal neurons responded in different ways. In one half of the neurons, all induced synaptic potentials were blocked. This suggests that most GABAergic intrinsic connections between neostriatal neurons are activated indirectly by 4-AP. 4-AP would first activate extrinsic glutamatergic afferents and these in turn would activate GABAergic intrinsic neurons and connections. 6. In the remaining half of the recorded neurons, administration of CNQX plus D-APV blocked most, but not all of the 4-AP-induced synaptic potentials. The synaptic potentials that remained had a characteristic pattern: they were high amplitude, rhythmic, bursts of synaptic potentials. They were blocked by BIC (5 mu M) but not by mecamylamine(>10 mu M). This suggests that these bursts of synaptic potentials were GABAergic and generated by intrinsic neurons. Therefore these neurons would not innervate all neostriatal neurons equally but just a subset of them. 7. Records from an identified aspiny neostriatal interneuron, obtained from the same preparation, are shown. This interneuron fired in bursts and is morphologically and physiologically similar to the recently described, fast spiking, parvalbumin immunoreactive, GABAergic, aspiny interneuron of the neostriatum. It then is concluded that this interneuron is functional in the slice preparation. Further, the hypothesis that it is the source of the synaptic potential trains is supported. In this case, 4-AP would be able to activate this interneuron, independently of extrinsic excitatory afferents. 8. In conclusion, 4-AP actions disclosed important aspects of the intrinsic circuitry of the mammalian neostriatum: first, not all neostriatal neurons might be innervated by intrinsic GABAergic interneurons. Second, GABA connections between most neostriatal neurons need extrinsic excitatory inputs to be active.