# Paradoxical facilitation of asynchronous neurotransmitter release accompanies depression of synchronous release at excitatory hippocampal synapses in culture

#### Abstract

Short-term plasticity of central nervous system synapses resulting from single action potentials or short trains of action potentials may modulate the normal synaptic transfer of information and the effective connectivity between neurons in the central nervous system. We have utilized paired whole cell patch clamp recordings to examine the short-term plasticity of excitatory synapses between pairs of cultured hippocampal neurons. These excitatory synapses display paired pulse depression that often lasts more than 4 seconds, and tetanic and posttetanic depression as well. Evidence for a presynaptic mechanism of frequency-dependent depression includes similar depression with activation of AMPA, NMDA or both receptors, attenuation of depression with lowering of extracellular $\rm Ca\sp{2+}/Mg\sp{2+}$ concentration ratio, and lack of a significant change in the distribution of mEPSC amplitudes following paired pulse or tetanic stimulation. Our data also demonstrate that the depression of EPSCs observed in paired-pulses or high-frequency trains between hippocampal neurons in culture occurs independent of activation of MCPG-sensitive presynaptic mGluRs, APV-sensitive NMDA autoreceptors, or CNQX-sensitive AMPA autoreceptors. A paradoxical increase in mEPSC frequency accompanied both single and multiple stimuli, and this mEPSC increase was facilitated during paired stimuli, even when the evoked synchronous release was depressed. Both the activity-dependent depression of evoked EPSCs and facilitation of asynchronous mEPSC release were dependent on Ca$\sp{2+}$ accumulation in the nerve terminal. However, the calcium-dependent mechanisms underlying these two processes could be distinguished by the differential effects of two membrane-permeant calcium chelators, BAPTA-AM and EGTA-AM. Frequency-dependent depression of evoked EPSCs involves a rapid rise in intraterminal Ca$\sp{2+}$ which likely triggers a process which proceeds in a calcium-independent manner, while the asynchronous release may be more directly linked to a sustained increase in intraterminal Ca$\sp{2+}$.

Neurology

#### Recommended Citation

Cummings, Dana D, "Paradoxical facilitation of asynchronous neurotransmitter release accompanies depression of synchronous release at excitatory hippocampal synapses in culture" (1996). Dissertations available from ProQuest. AAI9627908.
https://repository.upenn.edu/dissertations/AAI9627908

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