PAIRED-PULSE DEPRESSION IN CULTURED HIPPOCAMPAL-NEURONS IS DUE TO A PRESYNAPTIC MECHANISM INDEPENDENT OF GABA(B) AUTORECEPTOR ACTIVATION

Most rapid synaptic inhibition in the vertebrate forebrain is mediated by GABA acting via GABA(A) and GABA(B) postsynaptic receptors. GABAer gic neurotransmission exhibits frequency-dependent modulation; sequent ial inhibitory postsynaptic currents (IPSCs) evoked with interstimulus intervals between 25 msec and 4 sec routinely result in the attenuati on of the amplitude of the second IPSC. This form of synaptic plastici ty is known as paired pulse depression (PPD). The mechanism of PPD is presently unknown and the experiments performed in this study were des igned to determine directly the location of the mechanism of PPD in hi ppocampal neurons maintained in low-density tissue culture. Evoked IPS Cs were recorded between pairs of cultured neurons grown in relative i solation that were simultaneously being recorded with the whole-cell, patch-clamp technique. It was therefore possible to measure miniature IPSCs (mIPSCs) originating from the same synapses that were being stim ulated to evoke release. PPD occurred routinely in this system, but th e amplitudes of mIPSCs following IPSCs were unchanged. These results i ndicate that a presynaptic mechanism mediates PPD. The inability of GA BA(B) receptor antagonists to block PPD revealed that this form of pre synaptic plasticity was not due to autoinhibition of transmitter relea se via activation of presynaptic GABA(B) receptors. However, manipulat ions that significantly lowered the probability of release of neurotra nsmitter during the first action potential of a trial (e.g., lower cal cium or baclofen) prevented the development of PPD. These results indi cate that, under baseline conditions, the quantal content for IPSCs is relatively large for a single action potential, but the quantal conte nt rapidly decreases, such that subsequent action potentials consisten tly result in much smaller IPSCs for periods as long as 4 sec.