Thalamic reticular nucleus in the pathophysiology of schizophrenia

Mechanistic analyses on schizophrenia have traditionally focused on corticolimbic structures such as the prefrontal cortex, hippocampus, and amygdala, given their established roles in cognition. However, the thalamus, a critical hub that interconnects these regions, has garnered comparatively less attention. Of particular interest is the thalamic reticular nucleus, which plays a crucial role in cognition and sensory processing through its connections with the dorsomedial thalamic nucleus and the prefrontal cortex. A potential role of the thalamic reticular nucleus in schizophrenia has been suggested in a few reports; however, recent analyses have identified a specific link between the thalamic reticular nucleus and layer 5 neurons of the prefrontal cortex, a relationship highlighted by our group's earlier findings from 2012, which demonstrated that bilateral thalamic reticular nucleus lesions in adult rats caused neuronal atrophy in these cortical neurons. Building on this foundation, this manuscript explores the role of the thalamic reticular nucleus in schizophrenia neurobiology by reviewing its functional neuroanatomy, its integration within the corticolimbic system, and mechanisms of its potential involvement in the disease. This hypothesis is further developed by describing our novel findings from rats with neonatal ventral hippocampus lesion, widely considered a developmental model for schizophrenia. For the first time, we report dendritic spine pathology in thalamic reticular nucleus neurons, characterized by reduced spine density and a lower proportion of mushroom spines. Furthermore, we demonstrate a decrease in the density of parvalbumin-positive cells within the thalamic reticular nucleus in the neonatal ventral hippocampus lesion model. Together, these findings suggest significant alterations in the corticolimbic network and position the thalamic reticular nucleus as a complex yet promising mechanistic contributor to the neurobiology of schizophrenia.