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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-PV-TeLC and PFC-Lesion animals show impaired reversal learning.Both PFC-PV-GFP (n = 15) and PFC-PV-TeLC (n = 17) (A) and PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals (B) learn the location of the hidden platform in an open field water maze as indicated by 1) the reduction in path length to platform over the 5 day training period and 2) the amount of time spent in the target quadrant in a probe trial after training (insets). (C) PFC-PV-TeLC and (D), PFC-Lesion animals show a deficit in reversal learning as indicated by a delay in path length reduction during 4 days of reversal training (R1-4). All groups spent significantly more time in the new target quadrant in a probe trial after reversal learning (insets in C and D). (E,F) Example traces of path taken by PFC-PV-GFP (E, green), PFC-PV-TeLC (E, blue), PFC-Saline (F, grey) and PFC-Lesion (F, red) animals on the third day of reversal training. The original platform location is indicated as a hollow circle, the new platform location as filled circle. Note the increased length around the original platform location of PFC-PV-TeLC and PFC-Lesion animals compared to respective controls. Data are mean ± s.e.m.
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f4: PFC-PV-TeLC and PFC-Lesion animals show impaired reversal learning.Both PFC-PV-GFP (n = 15) and PFC-PV-TeLC (n = 17) (A) and PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals (B) learn the location of the hidden platform in an open field water maze as indicated by 1) the reduction in path length to platform over the 5 day training period and 2) the amount of time spent in the target quadrant in a probe trial after training (insets). (C) PFC-PV-TeLC and (D), PFC-Lesion animals show a deficit in reversal learning as indicated by a delay in path length reduction during 4 days of reversal training (R1-4). All groups spent significantly more time in the new target quadrant in a probe trial after reversal learning (insets in C and D). (E,F) Example traces of path taken by PFC-PV-GFP (E, green), PFC-PV-TeLC (E, blue), PFC-Saline (F, grey) and PFC-Lesion (F, red) animals on the third day of reversal training. The original platform location is indicated as a hollow circle, the new platform location as filled circle. Note the increased length around the original platform location of PFC-PV-TeLC and PFC-Lesion animals compared to respective controls. Data are mean ± s.e.m.

Mentions: Cognitive flexibility is impaired in schizophrenia and after PFC lesion41424344. We investigated the relevance of prefrontal PVIs for cognitive flexibility in a reversal learning task in the water maze3637. After initial spatial training (5 days, 4 trials/day) the platform was re-located to the opposite quadrant and mice underwent another 4 days (4 trials/day) of reversal training. During initial training PFC-PV-TeLC and PFC-Lesion mice learned the platform location as well as their respective controls as indicated by the reduction in path length (PFC-PV-TeLC/PFC-PV-GFP, day effect: F(4,120) = 45; p < 0.0001, no effect with group as factor: F’s < 1; PFC-Lesion/PFC-Saline, day effect: F(4,80) = 28; p < 0.0001; no effect with group as factor: F’s < 1) (Fig. 4A,B; see also Fig. 5) and the amount of time spent in the target quadrant during probe trials (t’s < 1.4) (Fig. 4 insets in A,B), indicating that spatial reference memory per se does not depend on the PFC3536. In contrast, during reversal, PFC-PV-TeLC and PFC-Lesion mice needed more time to learn the new platform location although this was only significant for PFC-PV-TeLC mice (PFC-PV-TeLC vs. PFC-PV-GFP, day effect F(3,84) = 24; p < 0.001; group effect F(4,84) = 8.8; p = 0.006; and PFC-Lesion vs. PFC-Saline, F(3,60) = 2.1; p = 0.16) (Fig. 4C–F). The deficit was transient as PFC-PV-TeLC mice performed as well as controls in the probe trial after over-training (t’s < 1.1) (Fig. 4 insets in C,D). We confirmed these deficits by analyzing two additional parameters. 1) The number of trials to attain floor level (4m path length, derived from Fig. 4) in two consecutive trials was not different between PFC-PV-TeLC or PFC-Lesion groups and their controls (Fig. 5A,B; t’s < 1.4) during initial training, but was significantly higher in reversal trials (Fig. 5A,B, t’s > 1.7; p’s ≤ 0.05). 2) We established the percentage of subjects meeting criterion (4m path length) for each trial during both training phases (Fig. 5C–F). During initial training we detected small differences between PFC-PV-TeLC or PFC-Lesion animals and their respective controls (a mild delay or acceleration in learning, respectively; Fig. 5C,D). However, all subjects met criterion at completion of acquisition. During reversal both PFC-PV-TeLC and PFC-Lesion mice showed a deficit in learning the new platform location (Fig. 5E,F). However, whereas PFC-PV-TeLC mice met reversal criterion upon overtraining, more than 30% of PFC-Lesion mice failed to do so. These results suggest that PVIs contribute to prefrontal operations involved in the inhibition of previously learned responses.


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-PV-TeLC and PFC-Lesion animals show impaired reversal learning.Both PFC-PV-GFP (n = 15) and PFC-PV-TeLC (n = 17) (A) and PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals (B) learn the location of the hidden platform in an open field water maze as indicated by 1) the reduction in path length to platform over the 5 day training period and 2) the amount of time spent in the target quadrant in a probe trial after training (insets). (C) PFC-PV-TeLC and (D), PFC-Lesion animals show a deficit in reversal learning as indicated by a delay in path length reduction during 4 days of reversal training (R1-4). All groups spent significantly more time in the new target quadrant in a probe trial after reversal learning (insets in C and D). (E,F) Example traces of path taken by PFC-PV-GFP (E, green), PFC-PV-TeLC (E, blue), PFC-Saline (F, grey) and PFC-Lesion (F, red) animals on the third day of reversal training. The original platform location is indicated as a hollow circle, the new platform location as filled circle. Note the increased length around the original platform location of PFC-PV-TeLC and PFC-Lesion animals compared to respective controls. Data are mean ± s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: PFC-PV-TeLC and PFC-Lesion animals show impaired reversal learning.Both PFC-PV-GFP (n = 15) and PFC-PV-TeLC (n = 17) (A) and PFC-Saline (n = 9) and PFC-Lesion (n = 13) animals (B) learn the location of the hidden platform in an open field water maze as indicated by 1) the reduction in path length to platform over the 5 day training period and 2) the amount of time spent in the target quadrant in a probe trial after training (insets). (C) PFC-PV-TeLC and (D), PFC-Lesion animals show a deficit in reversal learning as indicated by a delay in path length reduction during 4 days of reversal training (R1-4). All groups spent significantly more time in the new target quadrant in a probe trial after reversal learning (insets in C and D). (E,F) Example traces of path taken by PFC-PV-GFP (E, green), PFC-PV-TeLC (E, blue), PFC-Saline (F, grey) and PFC-Lesion (F, red) animals on the third day of reversal training. The original platform location is indicated as a hollow circle, the new platform location as filled circle. Note the increased length around the original platform location of PFC-PV-TeLC and PFC-Lesion animals compared to respective controls. Data are mean ± s.e.m.
Mentions: Cognitive flexibility is impaired in schizophrenia and after PFC lesion41424344. We investigated the relevance of prefrontal PVIs for cognitive flexibility in a reversal learning task in the water maze3637. After initial spatial training (5 days, 4 trials/day) the platform was re-located to the opposite quadrant and mice underwent another 4 days (4 trials/day) of reversal training. During initial training PFC-PV-TeLC and PFC-Lesion mice learned the platform location as well as their respective controls as indicated by the reduction in path length (PFC-PV-TeLC/PFC-PV-GFP, day effect: F(4,120) = 45; p < 0.0001, no effect with group as factor: F’s < 1; PFC-Lesion/PFC-Saline, day effect: F(4,80) = 28; p < 0.0001; no effect with group as factor: F’s < 1) (Fig. 4A,B; see also Fig. 5) and the amount of time spent in the target quadrant during probe trials (t’s < 1.4) (Fig. 4 insets in A,B), indicating that spatial reference memory per se does not depend on the PFC3536. In contrast, during reversal, PFC-PV-TeLC and PFC-Lesion mice needed more time to learn the new platform location although this was only significant for PFC-PV-TeLC mice (PFC-PV-TeLC vs. PFC-PV-GFP, day effect F(3,84) = 24; p < 0.001; group effect F(4,84) = 8.8; p = 0.006; and PFC-Lesion vs. PFC-Saline, F(3,60) = 2.1; p = 0.16) (Fig. 4C–F). The deficit was transient as PFC-PV-TeLC mice performed as well as controls in the probe trial after over-training (t’s < 1.1) (Fig. 4 insets in C,D). We confirmed these deficits by analyzing two additional parameters. 1) The number of trials to attain floor level (4m path length, derived from Fig. 4) in two consecutive trials was not different between PFC-PV-TeLC or PFC-Lesion groups and their controls (Fig. 5A,B; t’s < 1.4) during initial training, but was significantly higher in reversal trials (Fig. 5A,B, t’s > 1.7; p’s ≤ 0.05). 2) We established the percentage of subjects meeting criterion (4m path length) for each trial during both training phases (Fig. 5C–F). During initial training we detected small differences between PFC-PV-TeLC or PFC-Lesion animals and their respective controls (a mild delay or acceleration in learning, respectively; Fig. 5C,D). However, all subjects met criterion at completion of acquisition. During reversal both PFC-PV-TeLC and PFC-Lesion mice showed a deficit in learning the new platform location (Fig. 5E,F). However, whereas PFC-PV-TeLC mice met reversal criterion upon overtraining, more than 30% of PFC-Lesion mice failed to do so. These results suggest that PVIs contribute to prefrontal operations involved in the inhibition of previously learned responses.

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