Actions of proline at receptors and synapses

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Disturbances in brain handling of the amino acid proline are linked to a wide variety neurological and behavioral disorders including schizophrenia, autism, epilepsy, intellectual disability, and depression. Although proline has been suggested to be a candidate neurotransmitter, a demonstration of a prolinergic component of synaptic has been lacking. Proline is thought to mediate its action, in part, via activation of ionotropic glutamate receptors, which mediate the majority of synaptic transmission in the central nervous system. Yet, the actions of proline at glutamate receptors and synaptic transmission are not well understood. We hypothesize that the proline sensitivity of ionotropic glutamate receptors varies with subunit composition. Moreover, we propose that prolinergic transmission can be demonstrated by pharmacologically probing transmission between neurons that express SLC6A7, the high-affinity proline transporter responsible for a majority of synaptic proline uptake, and its postsynaptic partners. We will use a combination of electrophysiological, molecular, immunocytochemical, and imaging methods we will examine: 1) the pharmacological profile of proline at recombinant ionotropic glutamate receptors with distinct subunit compositions; 2) the preferred hippocampal cell types that are targets of putative prolinergic neurons; and 3) the how synaptically evoked proline accumulations shape glutamatergic transmission. Collectively, these studies will fill in major gaps in our knowledge regarding the actions of proline at glutamate receptors and synapses where prolinergic transmission likely occurs.