Fig. 2: Diagram displaying interaction between pyramidal neurons and parvalbumin interneurons (PVI) and possible targets for intervention in schizophrenia spectrum disorders (SSD).
PVI primarily exert inhibitory effects via synapses onto the perisomatic region of pyramidal cells. Gamma-aminobutyric acid (GABAA) receptors on the postsynaptic membrane receive GABA signalling from the PVI. A possible mechanism to compensate for the loss of PVI function is to increase postsynaptic GABA transmission via GABAA receptor modulation. PVI receive input via N-methyl-D-aspartic acid receptors (NMDAR) and α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPAR). Another possible mechanism leading to excitation/inhibition imbalances is the hypofunction of NMDAR on PVI, leading to reduced inhibition of pyramidal cells and increased glutaminergic transmission. A potential method to correct this is to increase the activity of the NMDAR. Allostatic modulation of AMPAR facilitates the removal of magnesium from NMDAR and, therefore, may also improve NMDAR signalling. Another possible approach is to reduce pre-synaptic glutamate release from pyramidal cells via positive allostatic modulation of metabotropic glutamate receptors (mGlu2/3). Finally oxidative stress can lead to dysfunction and loss of PVI, therefore antioxidants and anti-inflammatory agents have been investigated in SSD.
