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

Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KL, Foggetti A, Crouch B, Riedel G, Wulff P - Sci Rep (2015)

Bottom Line: It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

PFC-Lesion but not PFC-PV-TeLC mice show impaired social behavior and amphetamine hypersensitivity.(A,B) Quantification of time spent interacting with a conspecific stranger (S1) and an empty chamber (E) in a 3-chamber social preference test. (A) PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals spent significantly more time interacting with a conspecific mouse than with an empty chamber. (B) PFC-Lesion animals (n = 13) do not show a significant preference for social interaction. Example traces in (A,B) illustrate the travelled path. Increased density in the stranger compartment of PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline (n = 9) but not Lesion animals indicates preference for social interaction. (C,D) Discrimination between a novel (S2) and a familiar (S1) conspecific. PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline animals spent significantly more time with the novel mouse indicating social recognition. PFC-Lesion animals did not distinguish between novel and familiar animals. Dashed line indicates level where equal time is spent with familiar and stranger animals. (E,F) Response to amphetamine. (E) Path length in an open field of PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals. Dashed line indicates amphetamine administration. Both groups show enhanced locomotor activity after amphetamine administration. Insets show cumulated path length during the amphetamine activity period. (F) PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals before and after amphetamine administration. Both groups show enhanced locomotor activity after receiving amphetamine but PFC-Lesion animals show a hypersensitivity as indicated by increased peak locomotor activity (inset) and slower decay kinetics. Data are mean ± s.e.m. *P < 0.05; **p < 0.01; ***p < 0.001.
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f6: PFC-Lesion but not PFC-PV-TeLC mice show impaired social behavior and amphetamine hypersensitivity.(A,B) Quantification of time spent interacting with a conspecific stranger (S1) and an empty chamber (E) in a 3-chamber social preference test. (A) PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals spent significantly more time interacting with a conspecific mouse than with an empty chamber. (B) PFC-Lesion animals (n = 13) do not show a significant preference for social interaction. Example traces in (A,B) illustrate the travelled path. Increased density in the stranger compartment of PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline (n = 9) but not Lesion animals indicates preference for social interaction. (C,D) Discrimination between a novel (S2) and a familiar (S1) conspecific. PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline animals spent significantly more time with the novel mouse indicating social recognition. PFC-Lesion animals did not distinguish between novel and familiar animals. Dashed line indicates level where equal time is spent with familiar and stranger animals. (E,F) Response to amphetamine. (E) Path length in an open field of PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals. Dashed line indicates amphetamine administration. Both groups show enhanced locomotor activity after amphetamine administration. Insets show cumulated path length during the amphetamine activity period. (F) PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals before and after amphetamine administration. Both groups show enhanced locomotor activity after receiving amphetamine but PFC-Lesion animals show a hypersensitivity as indicated by increased peak locomotor activity (inset) and slower decay kinetics. Data are mean ± s.e.m. *P < 0.05; **p < 0.01; ***p < 0.001.

Mentions: Impairments in social function are common after prefrontal lesions and a component of the negative symptomatology in schizophrenia24546. Similarly, interference with PFC function in rodents has been shown to reduce social interaction4748. We tested PFC-PV-TeLC, PFC-Lesion and control animals for sociability and social recognition in a 3-chamber social preference test49. During sociability testing PFC-Lesion animals showed strongly reduced interaction with the conspecific animal (p = 0.003; t = 3.57) (Fig. 6B). However, PFC-PV-TeLC mice displayed similar levels of social interaction as PFC-PV-GFP control animals (p = 0.15; t = 1.59) (Fig. 6A). A similar pattern evolved in the second phase, where both control groups and PFC-PV-TeLC mice spent significantly more time with the unfamiliar than with the familiar animal (p = 0.003; t = 3.57 for PFC-PV-TeLC; p = 0.04; t = 1.97 for PFC-PV-GFP; p = 0.04; t = 2.00 for PFC-Saline), indicating intact social memory and a preference for social novelty (Fig. 6C,D). In contrast PFC-Lesion animals did not discriminate between familiar and unfamiliar mice (p = 0.3; t < 1) (Fig. 6D).


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

Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KL, Foggetti A, Crouch B, Riedel G, Wulff P - Sci Rep (2015)

PFC-Lesion but not PFC-PV-TeLC mice show impaired social behavior and amphetamine hypersensitivity.(A,B) Quantification of time spent interacting with a conspecific stranger (S1) and an empty chamber (E) in a 3-chamber social preference test. (A) PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals spent significantly more time interacting with a conspecific mouse than with an empty chamber. (B) PFC-Lesion animals (n = 13) do not show a significant preference for social interaction. Example traces in (A,B) illustrate the travelled path. Increased density in the stranger compartment of PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline (n = 9) but not Lesion animals indicates preference for social interaction. (C,D) Discrimination between a novel (S2) and a familiar (S1) conspecific. PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline animals spent significantly more time with the novel mouse indicating social recognition. PFC-Lesion animals did not distinguish between novel and familiar animals. Dashed line indicates level where equal time is spent with familiar and stranger animals. (E,F) Response to amphetamine. (E) Path length in an open field of PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals. Dashed line indicates amphetamine administration. Both groups show enhanced locomotor activity after amphetamine administration. Insets show cumulated path length during the amphetamine activity period. (F) PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals before and after amphetamine administration. Both groups show enhanced locomotor activity after receiving amphetamine but PFC-Lesion animals show a hypersensitivity as indicated by increased peak locomotor activity (inset) and slower decay kinetics. Data are mean ± s.e.m. *P < 0.05; **p < 0.01; ***p < 0.001.
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Related In: Results  -  Collection

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f6: PFC-Lesion but not PFC-PV-TeLC mice show impaired social behavior and amphetamine hypersensitivity.(A,B) Quantification of time spent interacting with a conspecific stranger (S1) and an empty chamber (E) in a 3-chamber social preference test. (A) PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals spent significantly more time interacting with a conspecific mouse than with an empty chamber. (B) PFC-Lesion animals (n = 13) do not show a significant preference for social interaction. Example traces in (A,B) illustrate the travelled path. Increased density in the stranger compartment of PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline (n = 9) but not Lesion animals indicates preference for social interaction. (C,D) Discrimination between a novel (S2) and a familiar (S1) conspecific. PFC-PV-GFP, PFC-PV-TeLC and PFC-Saline animals spent significantly more time with the novel mouse indicating social recognition. PFC-Lesion animals did not distinguish between novel and familiar animals. Dashed line indicates level where equal time is spent with familiar and stranger animals. (E,F) Response to amphetamine. (E) Path length in an open field of PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) animals. Dashed line indicates amphetamine administration. Both groups show enhanced locomotor activity after amphetamine administration. Insets show cumulated path length during the amphetamine activity period. (F) PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals before and after amphetamine administration. Both groups show enhanced locomotor activity after receiving amphetamine but PFC-Lesion animals show a hypersensitivity as indicated by increased peak locomotor activity (inset) and slower decay kinetics. Data are mean ± s.e.m. *P < 0.05; **p < 0.01; ***p < 0.001.
Mentions: Impairments in social function are common after prefrontal lesions and a component of the negative symptomatology in schizophrenia24546. Similarly, interference with PFC function in rodents has been shown to reduce social interaction4748. We tested PFC-PV-TeLC, PFC-Lesion and control animals for sociability and social recognition in a 3-chamber social preference test49. During sociability testing PFC-Lesion animals showed strongly reduced interaction with the conspecific animal (p = 0.003; t = 3.57) (Fig. 6B). However, PFC-PV-TeLC mice displayed similar levels of social interaction as PFC-PV-GFP control animals (p = 0.15; t = 1.59) (Fig. 6A). A similar pattern evolved in the second phase, where both control groups and PFC-PV-TeLC mice spent significantly more time with the unfamiliar than with the familiar animal (p = 0.003; t = 3.57 for PFC-PV-TeLC; p = 0.04; t = 1.97 for PFC-PV-GFP; p = 0.04; t = 2.00 for PFC-Saline), indicating intact social memory and a preference for social novelty (Fig. 6C,D). In contrast PFC-Lesion animals did not discriminate between familiar and unfamiliar mice (p = 0.3; t < 1) (Fig. 6D).

Bottom Line: It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus