Synapse-specific contributions in the cortical pathology of schizophrenia

Abstract

Schizophrenia (SZ) is often described as a disease of neuronal connectivity. Cognitive processes such as working memory, which are particularly dependent on the proper functioning of complex cortical circuitry, are disturbed in the disease. Reciprocal connections between pyramidal neurons and interneurons, as well as dopaminergic innervations, form the basis for higher cognition in the cortex. Nonetheless, only a few review articles are available which address how each synapse operates, and is possibly disturbed in SZ, at least in part by mechanisms involving genetic susceptibility factors for SZ. In this review, we provide an overview of cortical glutamatergic, GABAergic, and dopaminergic circuitry, review SZ-associated deficits at each of these synapses, and discuss how genetic factors for SZ may contribute to SZ-related phenotypes deficits in a synapse-specific manner. Pinpointing the spatially and temporally distinct sites of action of putative SZ susceptibility factors may help us better understand the pathological mechanisms of SZ, especially those associated with synaptic functioning and neuronal connectivity.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…There is persuasive evidence linking dysfunction at the synapse level to schizophrenia pathophysiology (14,(31)(32)(33)(34). Alterations to synaptic microcircuitry within the DLPFC of patients with schizophrenia include reduced excitatory inputs at layer 3 pyramidal neurons, increases in neuronal density, and altered expression of synaptic proteins (31,35).…”

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

“…Aberrant synaptic pruning during adolescence has been suggested in the pathology of schizophrenia (7,(32)(33)(34). In accordance with this hypothesis, dynamic changes in brain morphology and glutamate signaling have also been reported in recent onset schizophrenia cases and subjects in the prodromal stages of schizophrenia (35,36).…”

Synapse-type-specific plasticity in local circuits

“…Furthermore, activity levels must be kept within reasonable bounds, and it is likely that one or several interneuron types specifically adjust their inhibitory influence according to key developmental events such as eye opening, or in pathological states such as physical trauma, inflammation, or epilepsy. Indeed, STSP dysfunction has been observed in a variety of disease states ranging from schizophrenia [74], Alzheimer's disease [75], to autism spectrum disorders [76,77], demonstrating that an understanding of the properties of STSP may be fundamental to treating neurological diseases.…”