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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

Neither PFC-PV-TeLC nor PFC-Lesion animals showed alterations during baseline behavioral assessment.Analysis of path length in the open field for (A), PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) and (B), PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals suggests normal baseline motor activity. (C,D) Time spent in the centre of an open field arena indicates no alterations in anxiety-related thigmotaxis. (E,F) The number of nose pokes during exploration of a hole-board arena is similar in all groups of mice indicating normal exploratory activity. Data are mean ± s.e.m.
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f2: Neither PFC-PV-TeLC nor PFC-Lesion animals showed alterations during baseline behavioral assessment.Analysis of path length in the open field for (A), PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) and (B), PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals suggests normal baseline motor activity. (C,D) Time spent in the centre of an open field arena indicates no alterations in anxiety-related thigmotaxis. (E,F) The number of nose pokes during exploration of a hole-board arena is similar in all groups of mice indicating normal exploratory activity. Data are mean ± s.e.m.

Mentions: Neither PFC-PV-TeLC nor PFC-Lesion mice showed obvious neurological deficits or alterations in locomotion and anxiety-related behavior (Fig. 2A-D). As deficits in working memory are a dominant cognitive symptom in both schizophrenia and PFC lesions4353839 we investigated the involvement of PVIs in the production of working memory. We implemented a hole-board-based working memory test by analyzing repeat investigations of previously explored holes. Although all groups of mice showed similar overall levels of nose pokes (Fig. 2E,F), indicating similar exploratory activity, both PFC-PV-TeLC and PFC-Lesion animals showed increased levels of repeat investigations (PFC-PV-TeLC vs. PFC-PV-GFP, p = 0.04; t = 1.97; PFC-Lesion vs. PFC-Saline, p = 0.04; t = 1.98) (Fig. 3A,B). This deficit was confirmed in a spontaneous alternation task in the Y-maze, where alternation levels were high in PFC-PV-GFP and PFC-Saline animals (70.0 ± 3.0% and 74.3 ± 4.1% respectively), but significantly lower in PFC-PV-TeLC and PFC-Lesion animals (56.9 ± 2.7% and 60.0 ± 2.3% respectively) (Fig. 3C,D). Both reinvestigation and spontaneous alternation probe a spontaneous on-line processing of information. To assess whether PVIs also contribute to temporally expanded forms of working memory, which are known to be impaired after PFC lesions4041, we used a delayed (60s) match-to-place test in a Y-maze configuration in the water maze, where the percentage of correct responses in match trials represents trial unique short-term memory26. Whereas PFC-PV-GFP animals showed significant improvement in match trials, PFC-PV-TeLC animals did not (Fig. 3E).


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)

Neither PFC-PV-TeLC nor PFC-Lesion animals showed alterations during baseline behavioral assessment.Analysis of path length in the open field for (A), PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) and (B), PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals suggests normal baseline motor activity. (C,D) Time spent in the centre of an open field arena indicates no alterations in anxiety-related thigmotaxis. (E,F) The number of nose pokes during exploration of a hole-board arena is similar in all groups of mice indicating normal exploratory activity. Data are mean ± s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660359&req=5

f2: Neither PFC-PV-TeLC nor PFC-Lesion animals showed alterations during baseline behavioral assessment.Analysis of path length in the open field for (A), PFC-PV-GFP (n = 8) and PFC-PV-TeLC (n = 10) and (B), PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals suggests normal baseline motor activity. (C,D) Time spent in the centre of an open field arena indicates no alterations in anxiety-related thigmotaxis. (E,F) The number of nose pokes during exploration of a hole-board arena is similar in all groups of mice indicating normal exploratory activity. Data are mean ± s.e.m.
Mentions: Neither PFC-PV-TeLC nor PFC-Lesion mice showed obvious neurological deficits or alterations in locomotion and anxiety-related behavior (Fig. 2A-D). As deficits in working memory are a dominant cognitive symptom in both schizophrenia and PFC lesions4353839 we investigated the involvement of PVIs in the production of working memory. We implemented a hole-board-based working memory test by analyzing repeat investigations of previously explored holes. Although all groups of mice showed similar overall levels of nose pokes (Fig. 2E,F), indicating similar exploratory activity, both PFC-PV-TeLC and PFC-Lesion animals showed increased levels of repeat investigations (PFC-PV-TeLC vs. PFC-PV-GFP, p = 0.04; t = 1.97; PFC-Lesion vs. PFC-Saline, p = 0.04; t = 1.98) (Fig. 3A,B). This deficit was confirmed in a spontaneous alternation task in the Y-maze, where alternation levels were high in PFC-PV-GFP and PFC-Saline animals (70.0 ± 3.0% and 74.3 ± 4.1% respectively), but significantly lower in PFC-PV-TeLC and PFC-Lesion animals (56.9 ± 2.7% and 60.0 ± 2.3% respectively) (Fig. 3C,D). Both reinvestigation and spontaneous alternation probe a spontaneous on-line processing of information. To assess whether PVIs also contribute to temporally expanded forms of working memory, which are known to be impaired after PFC lesions4041, we used a delayed (60s) match-to-place test in a Y-maze configuration in the water maze, where the percentage of correct responses in match trials represents trial unique short-term memory26. Whereas PFC-PV-GFP animals showed significant improvement in match trials, PFC-PV-TeLC animals did not (Fig. 3E).

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