Fig. 3: Neuromodulatory mechanisms in layer III dlPFC spines involve magnified calcium signaling that must be tightly regulated for healthy connectivity.
A There are multiple mechanisms to magnify calcium (Ca2+) signaling in layer III dlPFC spines. In addition to calcium entry through NMDAR, cAMP-PKA signaling magnifies internal calcium release from the smooth endoplasmic reticulum (known as the spine apparatus in the spines, pink) through ryanodine receptors (RyR) and IP3 receptors (IP3R), which serve as internal calcium channels. Calcium in turn increases cAMP production, propelling feedforward signaling. Moderate levels of calcium strengthen synaptic connectivity via depolarization of the postsynaptic density (PSD), but high levels of calcium-cAMP-PKA signaling open nearby potassium (K+) channels to weaken connectivity. B Calcium and cAMP-PKA signaling are regulated by multiple factors, including calbindin to bind cytosolic calcium, mGluR3, and α2A-AR to inhibit cAMP production, and phosphodiesterases PDE4A and PDE4D to catabolize cAMP once it is formed. The PDE4s are anchored in place by DISC1 (Disrupted In SChizophrenia). mGluR3 are stimulated by both glutamate and NAAG (N-Acetylaspartylglutamic acid (N-acetylaspartylglutamate), which is co-released with glutamate but selective for mGluR3. C Loss of regulation, e.g., through genetic alterations, aging, and/or inflammation causes weakening of PFC connectivity and neuronal firing. For example, GCPII (Glutamate carboxypeptidase II) catabolizes NAAG and is increased by inflammation, reducing mGluR3 regulation and weakening synaptic connectivity. PDE4s and calbindin are lost with ageing. See text for greater details.
