Sleep need driven oscillation of glutamate synaptic phenotype.

Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2-3. Silent synapses are absent, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. These sleep loss changes are recovered by sleep. Sleep genes are enriched for synaptic shaping cellular components controlling glutamate synapse phenotype, overlap with autism risk genes and are primarily observed in excitatory pyramidal neurons projecting intra-telencephalically. These genes are enriched with genes controlled by the transcription factor, MEF2c and its repressor, HDAC4. Thus, sleep genes under the influence of MEF2c and HDAC4, can provide a framework within which motor learning and training occurs mediated by sleep-dependent oscillation of glutamate-synaptic phenotypes.

Alpha1E-containing Ca2+ channels are involved in synaptic plasticity.

Long-term potentiation (LTP) is the most prominent model for the molecular and cellular mechanisms of learning and memory. Two main forms of LTP have been distinguished. The N-methyl-D-aspartate-receptor-dependent forms of LTP have been studied most extensively, whereas much less is known about N-methyl-D-aspartate-receptor-independent forms of LTP. This latter type of LTP was first described at the mossy fiber synapses in the hippocampus and subsequently at parallel fiber synapses in the cerebellum as well as at corticothalamic synapses. These presynaptic forms of LTP require a rise in the intraterminal calcium concentration, but the channel through which calcium passes has not been identified. By using pharmacological tools as well as genetic deletion, we demonstrate here that alpha1E-containing voltage-dependent calcium channels (VDCCs) shift the threshold for mossy fiber LTP. The channel is not involved in the expression mechanism, but it contributes to the calcium influx during the induction phase. Indeed, optical recordings directly show the presence and the function of alpha1E-containing VDCCs at mossy fiber terminals. Hence, a previously undescribed role for alpha1E-containing VDCCs is suggested by these results.

Cholinergic modulation of excitatory synaptic transmission in the CA3 area of the hippocampus.

Cholinergic innervation of the hippocampus has been implicated in memory formation and retrieval. Here we study cholinergic modulation of excitatory transmission in the CA3 area of the rat hippocampus. We used a combination of optical measurements of presynaptic calcium and electrophysiological measurements of synaptic currents to study associational-commissural (A/C) and mossy fiber (MF) synapses in brain slices. Direct synaptic modulation mediated by ACh receptors is only evident at the A/C synapse, where synaptic inhibition primarily reflects presynaptic calcium channel inhibition mediated by muscarinic receptors. MF synapses can, however, be indirectly modulated by muscarinic receptor activation. Muscarine elevates the firing rate of inhibitory cells, which increases GABA release and inhibits MF synapses by activating presynaptic GABA(B) receptors. Muscarine also depolarizes dentate granule cells and elevates their rate of firing. This leads to synaptic enhancement when combined with the use-dependent facilitation of MF synapses. In addition we were unable to evoke an increase in presynaptic calcium levels in MF boutons with local application of nicotinic receptor agonists. This finding does not support a leading hypothesis for MF modulation in which activation of presynaptic nicotinic receptors enhances transmission directly by elevating presynaptic calcium levels. However, indirect synaptic modulation could arise from nicotinic excitation of inhibitory neurons. Thus, to understand cholinergic modulation within the CA3 region, it is necessary to take into account secondary actions on synapses arising from other chemical messengers released by other cell types and to consider effects on firing patterns of presynaptic cells, which in turn influence release via use-dependent synaptic plasticity.

Glutamate and gamma-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus.

Mossy fiber synapses form the major excitatory input into the autoassociative network of pyramidal cells in the CA3 area of the hippocampus. Here we demonstrate that at the mossy fiber synapses, glutamate and gamma-aminobutyric acid (GABA) act as autaptic and heterosynaptic presynaptic inhibitory transmitters through metabotropic glutamate receptors (mGluRs) and GABAB receptors, respectively. Both GABAB receptors and mGluRs are activated through spillover from adjacent synapses. We demonstrate that glutamate spillover caused by brief tetanic activation of mossy fiber terminals remains intact at physiological temperatures. The activation of GABAB receptors increased the threshold for mossy fiber long-term potentiation (LTP), whereas activation of mGluRs did not have such an effect. We speculate that this heterosynaptic depression provides the mossy fiber synapses with a mechanism to efficiently shape input patterns into CA3, increasing the sparseness of the mossy fiber signal and enhancing the capacity and performance of the CA3 associative network. The increase in LTP threshold through activation of presynaptic inhibitory receptors imparts a piesynoptic associative nature to mossy fiber LTP.

Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors.

The classical view of fast chemical synaptic transmission is that released neurotransmitter acts locally on postsynaptic receptors and is cleared from the synaptic cleft within a few milliseconds by diffusion and by specific reuptake mechanisms. This rapid clearance restricts the spread of neurotransmitter and, combined with the low affinities of many ionotropic receptors, ensures that synaptic transmission occurs in a point-to-point fashion. We now show, however, that when transmitter release is enhanced at hippocampal mossy fibre synapses, the concentration of glutamate increases and its clearance is delayed; this allows it to spread away from the synapse and to activate presynaptic inhibitory metabotropic glutamate receptors (mGluRs). At normal levels of glutamate release during low-frequency activity, these presynaptic receptors are not activated. When glutamate concentration is increased by higher-frequency activity or by blocking glutamate uptake, however, these receptors become activated, leading to a rapid inhibition of transmitter release. This effect may be related to the long-term depression of mossy fibre synaptic responses that has recently been shown after prolonged activation of presynaptic mGluRs (refs 2, 3). The use-dependent activation of presynaptic mGluRs that we describe here thus represents a negative feedback mechanism for controlling the strength of synaptic transmission.