The role of phosphatidyl inositol-protein kinase C signaling in functional and structural alterations to rat prefrontal cortex: Implications for mental illness and aging

The working memory functions of the prefrontal cortex (PFC) depend on the interconnectivity of recurrent microcircuits. Dendritic spines on pyramidal neurons are a fundamental anatomical substrate of these excitatory networks. PFC pyramidal neuron spine loss is observed in advanced age, in mental illness, and following prolonged exposure to stress. These structural changes may explain weakened PFC regulation of thought, emotion, and action in these conditions. There is mounting evidence that biochemical and genetic alterations in these conditions have the potential to disconnect local networks via phosphatidyl inositol-protein kinase C (PI-PKC) intracellular signaling. Sustained dysregulation of this cascade may also underlie structural changes, including spine loss, as PFC gray matter loss in mental illness is reversed following treatment with lithium and valproic acid, and in vitro studies implicate PKC overactivation in spine loss. This dissertation is composed of three studies investigating the role of PI-PKC signaling in PFC morphological and cognitive integrity. The first two studies examined effects of sustained PKC dysregulation in working memory, spine density, and dendritic morphology in chronically stressed and aged rats. The third study investigated the role of inositol-1,4,5 trisphosphate (IP3) mediated intracellular calcium (Ca2+) release on working memory function to address the possibility that factors upstream of PKC influence PFC function. We found that inhibition of PKC rescues working memory impairments and reverses spine loss of pyramidal PFC neurons in chronically stressed and aged rats. Inhibition of IP3 receptor mediated Ca2+ release also improved working memory, and this is likely achieved, in part, through blocking small conductance Ca2+-activated potassium (SK) channels. We also present the first evidence of an association between the structural integrity of pyramidal neurons and working memory performance in the rat: a greater density of distal, apical spines predicted better working memory, indicating that the dendritic region most sensitive to stress is also critical for networks subserving cognitive processes. Taken together, these findings indicate that PI-PKC intracellular signaling is associated with PFC dysfunction and suggest that PKC inhibitors may be useful for neuroprotection and for the treatment of cognitive deficits in bipolar disorder and schizophrenia and in the elderly.