Abstract:
Glutamate is the major excitatory neurotransmitter in the mammalian brain. Once released into the synaptic cleft, glutamate is cleared within less than a millisecond through passive diffusion and active uptake. The efficiency of these processes depends on the morphology of the synapse and extracellular space and the spatial distribution of glutamate transporters, abundantly expressed in astrocytes. Only a perimeter of 50% of hippocampal excitatory synapses is by astrocytic membranes, leaving ample room for glutamate to act at non-synaptic sites. Glutamate spillover can lead to the activation of receptors expressed on neighboring GABAergic interneurons, a process that can be exacerbated by blocking glutamate transporters. Our slice physiology experiments show that glutamate spillover leads to heterosynaptic activation of presynaptic metabotropic glutamate receptors expressed at neighboring GABAergic terminals. Here, we show that this form of presynaptic modulation occurs at different types of GABAergic neurons targeting CA1 pyramidal cells. In addition, we provide an example of changes in synaptic strength that happen through various forms of modulation in CA1 pyramidal cells in the presence of Aβ42, a peptide that accumulates in the brain of patients affected by Alzheimer’s disease. By using a compartmental model of these cells, we explore the implications that concurrent changes in synaptic strength have on the firing output of the hippocampus. These findings shed light on the implications that small changes in synaptic strength have to regulate the activity of neuronal circuits implicated with learning, memory, and spatial navigation.
