Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

Abstract

Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice using region- and cell-type-selective expression of tetanus toxin light chain (TeLC) and compared the functional consequences of this manipulation with non-cell-type-selective perturbations of the same circuitry. By sampling for behavioral alterations that map onto distinct symptom categories in schizophrenia, we show that dysfunction of PVI signaling in the PFC specifically produces deficits in the cognitive domain, but does not give rise to PFC-dependent correlates of negative or positive symptoms. Our results suggest that distinct aspects of the complex symptomatology of PFC dysfunction in schizophrenia can be attributed to specific prefrontal circuit elements.

Parvalbumin-containing GABA cells and schizophrenia: experimental model based on targeted gene delivery through adeno-associated viruses

“…For the specific scientific questions we sought to answer, our choice was the PV-Cre line described previously in our studies (Hippenmeyer et al ., 2005; Murray et al ., 2011; 2015). We have utilized the method also to transfect AAV into other GABA-containing interneurons selectively expressing Cre recombinase (Woloszynowska-Fraser MU, Wulff P, Riedel G, unpublished data).…”

“…This is consistent with stress models of anxiety that have revealed a lowering of PV-GABA neurones in PFC of mice; this phenotype can be rescued by environmental enrichment (Sampedro-Piquero et al ., 2016). Although we have not mechanistically assessed the expression of this anxiety phenotype in PV-TeLc mice, our method has led to a lasting functional impairment of parvalbumin neurones in prefrontal regions (Murray et al ., 2015). Whether this can be rescued by treatment using antidepressive drugs or environmental enrichment remains to be determined.…”

“…This exploits the natural tendency of mice to visit alternate arms and we followed our previous protocol (Murray et al ., 2015). The maze consisted of three equally sized arms (A, B and C; each 60 cm long, 10 cm wide and 10 cm high) configured in a Y shape (angled at 120°).…”

“…We therefore proposed (Murray et al ., 2015) that a logical approach for mimicking in rodents the pathology in dlPFC of SZ patients is the selective inactivation of PV + GABAergic interneurons in the dlPFC homologue, that is the infralimbic and prelimbic PFC of the mouse. This approach has a strong translational component.…”

“…To this end, we generated adeno-associated viruses (AAVs) carrying an inverted green fluorescent protein (GFP)-tagged tetanus toxin light chain (TeLc; or GFP alone as control) reading frame in a flip-excision cassette (AAV-FLEX-TeLc and AAV-FLEX-GFP) (Murray et al ., 2011) by transfection of human embryonic kidney cells (HEK293) with the AAV backbone plasmids (McClure et al ., 2011; Murray et al ., 2011, 2015). TeLc is a bacterial neurotoxin that acts intracellularly (Gaisano et al ., 1994), by cleaving the vesicle-associated membrane protein-2 (VAMP-2).…”