Sinapsi Tripartita e Reti Perineuronali: la loro implicazione nella Schizofrenia

Schizophrenia (SCZ) is a severe and long-lasting mental disorder that affects approximately 1% of the world’s population. Nevertheless, its pathophysiology and etiology still remain unclear. In the last decades, alongside the coining of the term “Tripartite Synapses”, greater attention has been put into understanding the involvement of glia cells and neurotransmitter systems (e.g., glutamatergic, and GABAergic) in SCZ pathophysiology. Recent studies have largely demonstrated the crucial role of astrocytes which, having a strong impact on neural development and on neurotransmitters and extracellular matrix homeostasis, are specifically involved in many pathological mechanisms, especially those provoking cognitive impairment. In particular, dysfunction of astroglial adenosine A2 receptors (A2AR) led to an increased psychomotor response to MK-801, an antagonist of NMDA receptor, and reduced working memory. Those effects seem to be caused by a disrupted glutamate homeostasis, through the tight regulation of A2AR on the transporter GLT-1 activity. Furthermore, it has been described how the duplication of chromosome 16p11.2, resulting in the overactivation of the TAOK2-JNK signaling, causes dysfunctions and developmental abnormalities in cortical GABAergic interneurons and surrounding perineuronal nets (PNNs). In addition, studies discovered that the SAGA protein complex is specifically required to regulate, via transcription control, the composition and the signaling of the extracellular environment in peripheral glia. This mechanism occurs through epigenetic signaling during homeostatic plasticity, which happened to contribute, directly or indirectly, to the pathogenesis of schizophrenia. The importance of tripartite synapses in the pathophysiology of schizophrenia has just been uncovered, however, it surely deserves further investigation to discover relevant pharmacological treatments, especially for cognitive dysfunction.