L-proline and glutamatergic neurotransmission: clarifying the modulatory role of neuronal proline transporter in cognition.

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L-proline shares several properties with neurotransmitters. It has heterogeneous regional distribution in brain, a neuronal biosynthetic pathway, Ca++ dependent release upon depolarization, and high-affinity uptake mediated by the neuronal L-proline transporter PROT, which is expected to control extracellular levels of L-proline. However, no evidence exists for specific L-proline receptors in the CNS. Hence, the roles of L-proline and PROT in neurotransmission remain unknown. To determine the in vivo role of PROT, we have generated a PROT knock-out mouse line. These mice show behavioral differences in anxiety-like, locomotor activity and sensorimotor gating paradigms. In addition, alterations in expression levels of synaptic components of glutamatergic neurotransmission have been also identified, thus suggesting an important neuromodulator function in brain both for L-proline and PROT. The goal of this research project is to gain more insight into the specific functional roles of PROT in the CNS and into mechanisms that regulate its expression and functionality. Toward this goal, we will: (1) extend the analysis on the effects of PROT gene deletion on synaptic protein expression; (2) assess new behavioral differences in PROT−/− mice; (3) confirm the neuromodulator role of PROT in glutamatergic neurotransmission by electrophysiological analysis; (4) characterize the cellular localization, trafficking and function modulation of PROT in neurons.