POSTSYNAPTIC MECHANISMS UNDERLYING LONG-TERM DEPRESSION OF GABAERGIC TRANSMISSION IN NEURONS OF THE DEEP CEREBELLAR NUCLEI

1. The mechanisms underlying long-term depression (LTD) of gamma-amino butyric acid-A (GABA(A)) receptor-mediated synaptic transmission induc ed by 10-Hz stimulation of the inhibitory afferents were investigated using perforated and whole cell voltage-clamp recordings from neurons of the deep cerebellar nuclei (DCN). 2. LTD of inhibitory postsynaptic currents (IPSCs) was reliably induced when the 10-Hz stimulation was delivered under current-clamp conditions where the postsynaptic neuron al membrane was allowed to depolarize. 3. Currents elicited by local a pplications of the GABA(A) receptor agonist, 4,5,6,7-tetrahydroisoxazo lo [5,4-c]pyridin-3-ol hydrochloride (THIP) were also depressed during LTD. 4. LTD could be induced heterosynaptically and did not require t he activation of GABA(A) receptors during the 10-Hz stimulation. 5. In cells loaded with QX-314 and superfused with media containing 6-cyano -7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovaleric ac id (APV), a series of depolarizing pulses (50 mV, 200 ms) induced a su stained depression of the IPSC. However, this was not observed in cell s recorded with high bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid ( BAPTA)-containing pipette solutions or when they were exposed to the L -type Ca2+ channel antagonist, nitrendipine. 6. The 10-Hz-induced LTD was also inhibited by BAPTA and was significantly reduced when DCN cel ls were loaded with microcystin LR or treated with okadaic acid, both inhibitors of protein phosphatases. 7. These results indicate that inc reases in postsynaptic [Ca2+] and phosphatase activity can reduce the efficacy of GABA(A) receptor-mediated synaptic transmission.