LTP regulates burst initiation and frequency at mossy fiber-granule cell synapses of rat cerebellum: experimental observations and theoretical predictions

Long-term potentiation (LTP) is a synaptic change supposed to provide the cellular basis for learning and memory in brain neuronal circuits. Although specific LTP expression mechanisms could be critical to determine the dynamics of repetitive neurotransmission, this important issue remained largely unexplored. In this paper, we have performed whole cell patch-clamp recordings of mossy fiber-granule cell LTP in acute rat cerebellar slices and studied its computational implications with a mathematical model. During LTP, stimulation with short impulse trains at 100 Hz revealed earlier initiation of granule cell spike bursts and a smaller nonsignificant spike frequency increase. In voltage-clamp recordings, short AMPA excitatory postsynaptic current (EPSC) trains showed short-term facilitation and depression and a sustained component probably generated by spillover. During LTP, facilitation disappeared, depression accelerated, and the sustained current increased. The N-methyl-d-aspartate (NMDA) current also increased. In agreement with a presynaptic expression caused by increased release probability, similar changes were observed by raising extracellular Ca(2+)]. A mathematical model of mossy fiber-granule cell neurotransmission showed that increasing release probability efficiently modulated the first-spike delay. Glutamate spillover, by causing tonic NMDA and AMPA receptor activation, accelerated excitatory postsynaptic potential (EPSP) temporal summation and maintained a sustained spike discharge. The effect of increasing neurotransmitter release could not be replicated by increasing receptor conductance, which, like postsynaptic manipulations enhancing intrinsic excitability, proved very effective in raising granule cell output frequency. Independent regulation of spike burst initiation and frequency during LTP may provide mechanisms for temporal recoding and gain control of afferent signals at the input stage of cerebellar cortex.