Suppressed prefrontal neuronal firing variability and impaired social representation in IRSp53-mutant mice
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Evaluation Summary:
This paper is of interest for neuroscientists studying neocortical neural activity related to social behavior, with a connection to mouse models of neuropsychiatric disorders. The work provides new data on how loss-of-function of postsynaptic scaffolding and adaptor protein IRSp53 (encoded by the BAIAP2 gene) impacts prefrontal cortex activity and social interaction in mice. Overall, the experiments are properly controlled, although further analysis and interpretations are needed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Social deficit is a major feature of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder, but its neural mechanisms remain unclear. Here, we examined neuronal discharge characteristics in the medial prefrontal cortex (mPFC) of IRSp53/Baiap2-mutant mice, which show social deficits, during social approach. We found a decrease in the proportion of IRSp53-mutant excitatory mPFC neurons encoding social information, but not that encoding non-social information. In addition, the firing activity of IRSp53-mutant neurons was less differential between social and non-social targets. IRSp53-mutant excitatory mPFC neurons displayed an increase in baseline neuronal firing, but decreases in the variability and dynamic range of firing as well as burst firing during social and non-social target approaches compared to wild-type controls. Treatment of memantine, an NMDA receptor antagonist that rescues social deficit in IRSp53-mutant mice, alleviates the reduced burst firing of IRSp53-mutant pyramidal mPFC neurons. These results suggest that suppressed neuronal activity dynamics and burst firing may underlie impaired cortical encoding of social information and social behaviors in IRSp53-mutant mice.
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Evaluation Summary:
This paper is of interest for neuroscientists studying neocortical neural activity related to social behavior, with a connection to mouse models of neuropsychiatric disorders. The work provides new data on how loss-of-function of postsynaptic scaffolding and adaptor protein IRSp53 (encoded by the BAIAP2 gene) impacts prefrontal cortex activity and social interaction in mice. Overall, the experiments are properly controlled, although further analysis and interpretations are needed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Understanding neuronal mechanisms underlying social disorders is an important question in neuroscience. Using tetrode recording, Kim et al. revealed that the firing rates of excitatory mPFC neurons are increased but the dynamic range of firing and the proportion of burst activities were decreased in the presence of social targets in IRSp53-KO mice. This study provides a possible mechanistic explanation of why autistic mice have difficulties in responding to social targets and will be of interest.
The biggest criticism is that in the identified single-units in the mPFC of either WT or IRSp53 KO, only 10% were responsive to social and/or object targets, while 90% of the recorded units are not responsive to either target (Figure 7E). Consistently, the mean firing rate in E-E, fS-O and sS-O are similar in both …
Reviewer #1 (Public Review):
Understanding neuronal mechanisms underlying social disorders is an important question in neuroscience. Using tetrode recording, Kim et al. revealed that the firing rates of excitatory mPFC neurons are increased but the dynamic range of firing and the proportion of burst activities were decreased in the presence of social targets in IRSp53-KO mice. This study provides a possible mechanistic explanation of why autistic mice have difficulties in responding to social targets and will be of interest.
The biggest criticism is that in the identified single-units in the mPFC of either WT or IRSp53 KO, only 10% were responsive to social and/or object targets, while 90% of the recorded units are not responsive to either target (Figure 7E). Consistently, the mean firing rate in E-E, fS-O and sS-O are similar in both WT and KO mice (Figure 3-supplement 1E), indicating that the presence of social targets had little effect in regulating most of the recorded mPFC neurons. Therefore, it is hard to believe that the recorded mPFC neurons play an essential role in discriminating social targets. Although the authors found that the dynamic range of firing rates (Figure 3E), burst proportion/spike variability (Figure 4) were different between WT and KO mice, such differences may be due to general suppression of firing in the KO mice. The authors should ideally further examine whether the FR range and burst firing proportion are different between WT and KO in resting and non-social conditions.
The authors found that the average resting firing rates of excitatory mPFC neurons in awake IRSp53-KO mice are larger than that in WT mice (Figure 1C and 1D). These results oppose their previous findings obtained from anaesthetized mice (Chung et al., 2015, Figure 8b and 8c). However, no such difference was observed between awake and anaesthetized WT animals. The authors should comment on the differences between these findings.
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Reviewer #2 (Public Review):
The manuscript by Kim et al. studies activity of prefrontal neurons during simple social tasks in IRSp53-KO mice. These mice are proposed as a model of autism and have deficits in social interaction. The major findings are that in KO mice: 1) activity levels of putative excitatory neurons are elevated, 2) baseline firing rates are elevated but peak firing rates and variability of firing during social exploration are reduced resulting in a reduced dynamic range, 3) bursting in putative excitatory neurons during the social exploration task is reduced, 4) the normalized difference in firing rates near objects vs. social targets is smaller, and 5) a decreased proportion of neurons are classified as selective for social targets vs. objects.
Major strengths are the approach which records from many individual …
Reviewer #2 (Public Review):
The manuscript by Kim et al. studies activity of prefrontal neurons during simple social tasks in IRSp53-KO mice. These mice are proposed as a model of autism and have deficits in social interaction. The major findings are that in KO mice: 1) activity levels of putative excitatory neurons are elevated, 2) baseline firing rates are elevated but peak firing rates and variability of firing during social exploration are reduced resulting in a reduced dynamic range, 3) bursting in putative excitatory neurons during the social exploration task is reduced, 4) the normalized difference in firing rates near objects vs. social targets is smaller, and 5) a decreased proportion of neurons are classified as selective for social targets vs. objects.
Major strengths are the approach which records from many individual neurons in the prefrontal cortex of behaving mice, the findings of effects that are specific to putative excitatory neurons, and the link between changes in the firing rates of neurons and changes in how information about social behavior is encoded. Current weaknesses include: the discrimination index employed by the authors does not account for the possibility that changes in neural variability may compensate for the reduced dynamic range of individual neurons or measure information encoding at a population level; the relevance of this gene to autism is only supported by a case-control study; the relationship of the changes in neural activity to specific mechanisms is unclear; it is unclear whether these changes in neural simply co-occur with behavioral changes vs. whether there is a tight correlation or even causal relationship between them; and the magnitude of many of the effects is small.
Together the current findings do indicate a specific pattern of changes in firing rate which produce altered encoding of social information by prefrontal neurons in this mutant mouse.
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Reviewer #3 (Public Review):
Here Kim et al. record in the medial prefrontal cortex (mPFC) of IRSp53 knockout (KO) mice. They focused on evaluating activity patterns recorded with tetrodes in prelimbic (PrL), infralimbic (IL), and cingulate (Cg1) cortical regions of male adult wild-types and KOs, as animals interacted with other males or objects in a linear chamber. KO mice sniffed less and spent less time in the interaction zone on the social side vs object side during the first session, but sniff durations and dwell times were comparable for the second session. Recordings indicated that putative excitatory single-units from KO animals had a dampened dynamic range, statistically lower variability, and less bursting in the linear chamber compared to neurons from wild-types, with higher basal firing rates and smaller instantaneous …
Reviewer #3 (Public Review):
Here Kim et al. record in the medial prefrontal cortex (mPFC) of IRSp53 knockout (KO) mice. They focused on evaluating activity patterns recorded with tetrodes in prelimbic (PrL), infralimbic (IL), and cingulate (Cg1) cortical regions of male adult wild-types and KOs, as animals interacted with other males or objects in a linear chamber. KO mice sniffed less and spent less time in the interaction zone on the social side vs object side during the first session, but sniff durations and dwell times were comparable for the second session. Recordings indicated that putative excitatory single-units from KO animals had a dampened dynamic range, statistically lower variability, and less bursting in the linear chamber compared to neurons from wild-types, with higher basal firing rates and smaller instantaneous changes in the KOs during S-O sessions. These are interesting experiments and a really rich dataset, but I have some questions about both the robustness of the behavioral and neuronal results, as well as concerns that the analysis is at present just barely scratching the surface and thus not quite as enlightening as it potentially could be.
The authors state based on the results of Figure 1 that KO animals 'display social impairments', but I wonder if this is the only interpretation of their data. In Figure 1E, time spent sniffing the objects during the first S-O session is not significantly different between wild-types and KOs, although is much more variable in the KOs; similarly, social sniff times are also quite variable. These times are measured in tens to hundreds of seconds, likely enough time for animals to obtain a considerable amount of sensory information from their sniffing- perhaps the KO animals have somewhat stronger sniffs, or are faster at processing the olfactory information somewhere in the brain, requiring them to spend less time (around ~25% less time compared to wild-types) sniffing and remaining in the in-zone. I'm not sure this presents as 'social impairments' (plural).
There may be missed opportunities to say much more of potential interest about the unit activity. For one, I'm not sure why the classification in Figure 7 occurs at the end, rather than earlier in the manuscript, and the analysis of firing rate statistics done separately for 'social' vs 'non-social' neurons. I also wonder how a unit classification (i.e., of 'social' or not) holds up across sessions or episodes of engagement within a session, for example. If these really are 'social' units, presumably that aspect should be reliable across interactions with different mice. More importantly, the authors take the trouble to use machine learning methods to classify mouse part position, but they do not seem to do much with these data beyond marking where the mouse is in the track. The unit activity over time might be much more interesting if correlated with DeepLabCut-based analysis of what the animal was doing (or perhaps what the social interaction partner was doing) during the sessions. The analyses of Figures 5 and 6 are a step in this direction, but the authors really could have gone much further in terms of determining how the behavior relates to the activity, both of individual units and of simultaneously-recorded populations. Two more minor critiques are that the subregions of mPFC seem lumped together (neglecting any individual differences between PrL, IL, and Cg1), and that the reduction in variability in Figure 3, although technically statistically significant, seems marginal. Again, perhaps this would be improved by a cleaner analysis of relating the unit spike trains to moment-to-moment features of social interaction or other behaviors occurring during the S-O sessions.
What does the discrimination look like in Figure 6 if only 'social' units from wild-types and KOs were considered? A related question: do these changes in unit (and network) responses somehow directly result from the cellular function(s) of loss of IRSp53 (specifically in mPFC and/or elsewhere in the central nervous system)? Any chance that these results are not local to mPFC computations, but that the differences in firing in KOs is inherited from earlier regions providing, e.g., olfactory information eventually to mPFC?
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