A Role for Somatostatin-Positive Interneurons in Neuro-Oscillatory and Information Processing Deficits in Schizophrenia

Abstract

Alterations in neocortical GABAergic interneurons (INs) have been affiliated with neuropsychiatric diseases, including schizophrenia (SZ). Significant progress has been made linking the function of a specific subtype of GABAergic cells, parvalbumin (PV) positive INs, to altered gamma-band oscillations, which, in turn, underlie perceptual and feedforward information processing in cortical circuits. Here, we review a smaller but growing volume of literature focusing on a separate subtype of neocortical GABAergic INs, somatostatin (SST) positive INs. Despite sharing similar neurodevelopmental origins, SSTs exhibit distinct morphology and physiology from PVs. Like PVs, SSTs are altered in postmortem brain samples from multiple neocortical regions in SZ, although basic and translational research into consequences of SST dysfunction has been relatively sparse. We highlight a growing body of work in rodents, which now indicates that SSTs may also underlie specific aspects of cortical circuit function, namely low-frequency oscillations, disinhibition, and mediation of cortico-cortical feedback. SSTs may thereby support the coordination of local cortical information processing with more global spatial, temporal, and behavioral context, including predictive coding and working memory. These functions are notably deficient in some cases of SZ, as well as other neuropsychiatric disorders, emphasizing the importance of focusing on SSTs in future translational studies. Finally, we highlight the challenges that remain, including subtypes within the SST class.

Cortical ensembles selective for context

“…The fact that PFC suppression in our experiments augmented the V1 outputs to nondeviant stimuli suggests a mechanistic explanation for these clinical phenomena. Given what has been observed in schizophrenia patients with EEG recordings (16,47), a dysfunction of PFC inputs to V1, disorganization of local V1 ensembles (15), or altered inhibitory microcircuits (12) could each provide (nonmutually exclusive) explanations for mismatch deficits in the disorder.…”

“…Furthermore, whether and how such "prediction error" cells are selectively influenced by top-down inputs (i.e., backward projections) remains unknown as well. Such questions, and prediction error in general, carry major clinical significance since cortical SSA and DD are characteristically reduced in individuals with psychotic disorders (6,11), potentially due to diminished integration of top-down modulation (12) or destabilized local ensembles in V1 (13)(14)(15).…”

Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System

“…The glutamate N-methyl-D-aspartate receptors (NMDAR) on these interneurons are essential for the synchronized inhibition provided by the GABAergic interneurons to generate both GBO and TBO ( 26 – 28 ). These findings are supported by post-mortem studies that found a reduced number of PV + -interneurons in the frontal cortex of patients with schizophrenia ( 29 ) and a reduced number of SST + -interneurons in various cortical tissues (DLPFC, PFC, hippocampus) of patients with schizophrenia ( 30 ).…”

Current findings and perspectives on aberrant neural oscillations in schizophrenia

“…However, changes in interneurons are not limited to PV+ cells but involve several subtypes, such as somatostatin cells (SST), cholecystokinin basket cells (CCKb) and calretinin cells (CR) 48 . Accordingly, alterations in distinct interneuron‐subtypes could be potentially responsible for a wide range of impairments in neural oscillations and associated sensory and cognitive functions in schizophrenia 55,134 …”

“…Regarding low‐frequency oscillations, especially at theta‐frequencies, the role of somatostatin (SST) positive interneurons has been recently highlighted 55 . For example, pharmacogenetic silencing of STT interneurons in mouse visual cortex reduced mismatch‐negativity as well as the associated theta/alpha‐band responses 56 .…”