Mature parvalbumin interneuron function in prefrontal cortex requires activity during a postnatal sensitive period
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Canetta et al. explored the time-dependent effects of inhibition of parvalbumin-positive interneurons in the mouse prefrontal cortex on task learning and cognition. Overall, the study shows that prefrontal cortex PV cell activity during a sensitive period strongly modulates cognitive flexibility and network activity in the adult mouse. This study could progress our understanding of cell behavior in mouse prefrontal cortex.
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Abstract
In their seminal findings, Hubel and Wiesel identified sensitive periods in which experience can exert lasting effects on adult visual cortical functioning and behavior via transient changes in neuronal activity during development. Whether comparable sensitive periods exist for non-sensory cortices, such as the prefrontal cortex, in which alterations in activity determine adult circuit function and behavior is still an active area of research. Here, using mice we demonstrate that inhibition of prefrontal parvalbumin (PV)-expressing interneurons during the juvenile and adolescent period, results in persistent impairments in adult prefrontal circuit connectivity, in vivo network function, and behavioral flexibility that can be reversed by targeted activation of PV interneurons in adulthood. In contrast, reversible suppression of PV interneuron activity in adulthood produces no lasting effects. These findings identify an activity-dependent sensitive period for prefrontal circuit maturation and highlight how abnormal PV interneuron activity during development alters adult prefrontal circuit function and cognitive behavior.
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Author Response
Reviewer #3 (Public Review):
Canetta et al have characterized the developmental regulation of PV neurons in PFC. The experiments have been carefully conducted and even though this is an area of broad scientific interest, there are several issues that require consideration.
- The dosing regime of the CNO that has been employed will not provide persistent inhibition. Inhibition will operate on a 16 hr on/ 8 hr off cycle. Under such circumstances, it will be very difficult to rule out interspersed inhibition-related artifacts.
Our approach of twice daily injections of CNO is consistent with that of other publications that have used similar chemogenetic approaches to chronically alter activity1-3. However, the reviewer is correct that our twice daily CNO injection protocol may only intermittently inhibit PV cells, and it …
Author Response
Reviewer #3 (Public Review):
Canetta et al have characterized the developmental regulation of PV neurons in PFC. The experiments have been carefully conducted and even though this is an area of broad scientific interest, there are several issues that require consideration.
- The dosing regime of the CNO that has been employed will not provide persistent inhibition. Inhibition will operate on a 16 hr on/ 8 hr off cycle. Under such circumstances, it will be very difficult to rule out interspersed inhibition-related artifacts.
Our approach of twice daily injections of CNO is consistent with that of other publications that have used similar chemogenetic approaches to chronically alter activity1-3. However, the reviewer is correct that our twice daily CNO injection protocol may only intermittently inhibit PV cells, and it is possible that persistent inhibition might result in even stronger behavioral and circuit effects. However, it is also possible that more continuous CNO administration could lead to hM4DGi desensitization. Given these caveats, we respectfully submit that repeating all the experiments under conditions that would allow constant chronic dispensation of CNO (such as implantation of minipumps) is an excellent future experiment but currently outside the scope of this manuscript.
- The second major issue with the dosing regime is that it is long (35 days). Realizing that the development of PFC circuitry is complex but at P90, the animals will have been dosed for more than a third of their lives. How can the authors rule out compensatory changes that do not have anything to do with critical periods?
In future studies we hope to refine the timing of the developmental window mediating these long-term effects by comparing inhibiting during shorter developmental periods. Our current studies demonstrate that a 35-day window of inhibition during development, but not during adulthood, leads to long-lasting effects on behavior and prefrontal network function. If the developmental manipulation is more impactful because the manipulation represents a longer proportion of the animals’ lifetime, we would expect that the effect should wane as the animal gets older. However, for the rescue experiments that take place at P120 and P130, rather than P90, we still find that the Dev Inhibition animals are impaired, suggesting that it is not the proportion of the animals’ lifetime that has been inhibited, but the timing during which this inhibition occurs, that matters most.
- To this point, in the discussion first para line 8 - please change "transient" to something more suitable to reflect the duration of treatment.
We have replaced transient with reversible.
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eLife assessment
Canetta et al. explored the time-dependent effects of inhibition of parvalbumin-positive interneurons in the mouse prefrontal cortex on task learning and cognition. Overall, the study shows that prefrontal cortex PV cell activity during a sensitive period strongly modulates cognitive flexibility and network activity in the adult mouse. This study could progress our understanding of cell behavior in mouse prefrontal cortex.
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Reviewer #1 (Public Review):
Here, Canetta and collaborators tackled the following question: is PV cell activity during a sensitive period of neurodevelopment a critical factor in determining prefrontal cortex function in adult mice? To address this question, the authors used viral-based approaches to express chemogenetic molecules specifically in prefrontal cortical PV cells. PV cell activity was then reduced either between P14-50 or P94-P130, by daily CNO injections. To evaluate the effect of PV cell inhibition on prefrontal cortex function, the authors used two readouts: an odor- and texture-based attentional set-shifting task and an EEG-based analysis of brain oscillations. The authors report that mice experiencing PV cell inhibition between P14-50 show impaired responses in the extra-dimensional set-shifting part of the behavioral …
Reviewer #1 (Public Review):
Here, Canetta and collaborators tackled the following question: is PV cell activity during a sensitive period of neurodevelopment a critical factor in determining prefrontal cortex function in adult mice? To address this question, the authors used viral-based approaches to express chemogenetic molecules specifically in prefrontal cortical PV cells. PV cell activity was then reduced either between P14-50 or P94-P130, by daily CNO injections. To evaluate the effect of PV cell inhibition on prefrontal cortex function, the authors used two readouts: an odor- and texture-based attentional set-shifting task and an EEG-based analysis of brain oscillations. The authors report that mice experiencing PV cell inhibition between P14-50 show impaired responses in the extra-dimensional set-shifting part of the behavioral test and in the task-induced increase in the 65 Hz range power as adults. More in detail, the authors reported a statistically significant difference in the 65 Hz range power in the choice period of correct trials relative to baseline in both control and treated groups. However, the 65Hz frequency range power differed between the choice period of correct and incorrect trials in the naïve mice, but not in those that experienced PV cell inhibition between P14-50. None of these effects were present in mice that experienced PV cell inhibition as adults (P94-130). Of note, optogenetic mediated acute activation in adult mice improved both phenotypes in mice that experienced PV cell inhibition in the juvenile-adolescent periods, while it appeared to have no effects in naïve mice. Overall, these data sets demonstrate that prefrontal cortex PV cell activity during a sensitive period strongly modulates cognitive flexibility and network activity in the adult mouse. This set of carefully designed experiments in vivo constitutes a strength of the study.
In parallel, Canetta et al showed that spontaneous inhibitory postsynaptic currents (sIPSC) and PV cell-evoked IPSC are reduced in adult mice that experienced PV cell inhibition as juveniles. These alterations were not due to PV cell loss or PV cell synapse alterations. The authors reported a trend, which did not reach significance, towards lower PV expression levels. Overall, the cellular and molecular bases of PV cell deficits in adult mice following juvenile PV cell inhibition remain to be explored.
The major implication of this finding is that genetic and/or environmental risk factors affecting PV cell activity in juvenile/adolescent individuals likely contribute to the long term cognitive deficits that have been associated with neurodevelopmental disorders.
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Reviewer #2 (Public Review):
Canetta et al. investigated the time-dependent effects of inhibition of parvalbumin-positive interneurons in the mouse prefrontal cortex on task learning and cognition. The authors have used electrophysiology, optogenetics, behavioral paradigms, and histology. This study provides an interesting angle to understand cell behavior in the mouse prefrontal cortex, which eventually may help in therapies against schizophrenia.
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Reviewer #3 (Public Review):
Canetta et al have characterized the developmental regulation of PV neurons in PFC. The experiments have been carefully conducted and even though this is an area of broad scientific interest, there are several issues that require consideration.
The dosing regime of the CNO that has been employed will not provide persistent inhibition. Inhibition will operate on a 16 hr on/ 8 hr off cycle. Under such circumstances, it will be very difficult to rule out interspersed inhibition-related artifacts.
The second major issue with the dosing regime is that it is long (35 days). Realizing that the development of PFC circuitry is complex but at P90, the animals will have been dosed for more than a third of their lives. How can the authors rule out compensatory changes that do not have anything to do with critical …
Reviewer #3 (Public Review):
Canetta et al have characterized the developmental regulation of PV neurons in PFC. The experiments have been carefully conducted and even though this is an area of broad scientific interest, there are several issues that require consideration.
The dosing regime of the CNO that has been employed will not provide persistent inhibition. Inhibition will operate on a 16 hr on/ 8 hr off cycle. Under such circumstances, it will be very difficult to rule out interspersed inhibition-related artifacts.
The second major issue with the dosing regime is that it is long (35 days). Realizing that the development of PFC circuitry is complex but at P90, the animals will have been dosed for more than a third of their lives. How can the authors rule out compensatory changes that do not have anything to do with critical periods?
To this point, in the discussion first para line 8 - please change "transient" to something more suitable to reflect the duration of treatment.
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