Region specific knockdown of Parvalbumin or Somatostatin produces neuronal and behavioral deficits consistent with those observed in schizophrenia

Stephanie M Perez,Angela Boley,Daniel J Lodge

doi:10.1038/s41398-019-0603-6

Abstract

The anterior hippocampus and prefrontal cortex are regions linked to symptoms of schizophrenia. The anterior hippocampus is believed to be a key regulator of the mesolimbic dopamine system and is thought to be the driving force contributing to positive symptoms, while the prefrontal cortex is involved in cognitive flexibility and negative symptoms. Aberrant activity in these regions is associated with decreases in GABAergic markers, indicative of an interneuron dysfunction. Specifically, selective decreases are observed in interneurons that contain parvalbumin (PV) or somatostatin (SST). Here, we used viral knockdown in rodents to recapitulate this finding and examine the region-specific roles of PV and SST on neuronal activity and behaviors associated with positive, negative and cognitive symptoms. We found that PV and SST had differential effects on neuronal activity and behavior when knocked down in the ventral hippocampus (vHipp) or medial prefrontal cortex (mPFC). Specifically, SST or PV knockdown in the vHipp increased pyramidal cell activity of the region and produced downstream effects on dopamine neuron activity in the ventral tegmental area (VTA). In contrast, mPFC knockdown did not affect the activity of VTA dopamine neuron activity; however, it did produce deficits in negative (social interaction) and cognitive (reversal learning) domains. Taken together, decreases in PV and/or SST were sufficient to produce schizophrenia-like deficits that were dependent on the region targeted.

Highlights

A prominent pathology observed in individuals with schizophrenia are deficits in GABAergic neurotransmission[1,2,3,4]
Positive symptoms of the disease are attributed to dysfunction of the mesolimbic dopamine system, commonly observed in patients;[15,16] no evidence of a primary pathology in the dopamine neurons themselves exists[17]
The prefrontal cortex has been implicated as a key brain region involved in cognitive flexibility and the likely site of pathology for negative symptoms[31,32,33,34]

Summary

Introduction

A prominent pathology observed in individuals with schizophrenia are deficits in GABAergic neurotransmission[1,2,3,4]. Interneurons of the hippocampus and frontal cortex are largely comprised of independent subpopulations including those that express the calcium binding protein, parvalbumin (PV) or the neuropeptide, somatostatin (SST)[8]. PV-containing interneurons are fast-spiking and target the axon initial segment and cell body to regulate pyramidal cell firing. SST-containing interneurons exhibit a slow firing pattern and synapse on distal dendrites of pyramidal cell. A selective loss of PV and SST expression in hippocampal regions and frontal cortex have been observed post-mortem in brain tissue harvested from patients[4,9,10,11]. GABAergic interneuron deficits have been observed in analogous regions (ventral hippocampus and prefrontal cortex) in rodent models;[12,13,14] whether this contributes to, or is a cause of the disease has not been conclusively demonstrated

Methods

Results

Conclusion