Neuronal structural plasticity in the medial prefrontal cortexregulation by dopamine and psa-ncam

Resumen

Although there is a decline in brain plasticity across lifespan, neurons in certain areas of the adult brain retain the ability to undergo synaptic, dendritic and spine remodeling in response to different stimuli. This neuronal structural plasticity seems to be the basis for many cognitive processes and it is crucial for adaptive responses to aversive experiences and recovery from brain damage and disease. Among the numerous candidate molecules that have been identified for mediating this neuronal remodeling, cell adhesion molecules and, specially, the neural cell adhesion molecule (NCAM), are of particular interest. The addition of polysialic acid (PSA) to the NCAM is critical for the structural changes that underlie plasticity; not only because it prevents both homotypic and heterotypic NCAM bindings (anti-adhesive properties) but also because it interacts with a large number of molecules and signaling pathways that regulate synaptic strength. In consonance with this fact, PSA-NCAM expression, which is very high during brain development, is only retained in adult brain regions that display a high degree of neuronal structural plasticity. The medial prefrontal cortex (mPFC), which plays a crucial role in the control of cognitive function and is affected in several psychiatric and neurological disorders, is one of these plastic regions and PSA-NCAM expression can be found in neuropil elements and mature interneurons. The monoaminergic inputs to the mPFC are presumed to modulate these functions. In fact, changes in monoamine release in the mPFC have been described under conditions of stress, fear, or other affective stimuli and after working memory paradigms. Impairments of dopaminergic neurotransmission affecting mPFC function are implicated in the pathogenesis of several psychiatric disorders such as schizophrenia and major depression and also in the cognitive deficits and depressive symptoms frequently found in Parkinson's disease. Moreover, recent evidences indicate that changes in the structure and connectivity of neurons in the mPFC may also underlie the pathogenesis of these diseases and that pharmacological treatments may revert these changes by enhancing the plasticity of neuronal connections. Although most of the studies on neuronal structural plasticity have been focused on principal neurons, there is abundant evidence that, in these psychiatric and neurological disorders, interneurons and cortical inhibitory networks show abnormalities. Therefore, the neuronal plasticity of inhibitory networks may also be affected and PSA-NCAM might be involved. For this reason, the main objectives of this thesis are to study the influence of dopaminergic neurotransmission on the neuronal plasticity of prefrontocortical circuits and to evaluate whether changes in the expression of PSA-NCAM are responsible for these neuroplastic changes. We have found that many dopaminergic fibers were in close apposition to PSA-NCAM expressing interneurons which also co-expressed the dopamine D2 receptor. Both the lesion of the mesocortical dopamine pathway and the chronic treatment with a D2R antagonist, decrease the expression of PSA-NCAM, GAD67 (which mediates GABA synthesis) and synaptophysin (SYN) in the mPFC neuropil. Chronic treatment with a D2R agonist has the opposite effects and induced temporal differences in the expression of many other plasticity related genes. D2R agonist-induced increases in GAD67 and SYN neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. Cortical pyramidal neurons did not express PSA-NCAM, but parvalbumin (PV) axon terminals co-expressing this molecule could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and PV expressing puncta. PSA depletion did not block these effects, but reinforced the increase of PV expressing puncta, increases PV-SYN expressing puncta and decreases spine density in mPFC interneurons and pyramidal neurons, suggesting that the polysialilation of NCAM may regulate the perisomatic inhibition of mPFC pyramidal neurons and the structure of prefrontocortical neurons.