Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants

WT showed no systematic preference between reward magazine and CS during CS+ presentation before reversal.

“During CS+ presentation before reversal, WT interacted with the reward magazine (Figure 4A) as well as the CS itself (Figure 4C) with no systematic preference.”

Grooming trait value was not significantly correlated with EPM performance (ratio of time spent in closed vs open arms).

“To study the relation between grooming and anxiety, the grooming trait value was correlated with EPM performance (ratio of time spent in closed vs open arms), resulting in no significant correlation (Pearson R 2 of 0.16; NS; 95% CI −0.74 to 0.11) (Figure 2E).”

SAPAP3−/− spent less time in open arms on the EPM compared to WT.

“On the EPM, SAPAP3−/− spent less time in open arms (Figure 2B: 152.25 ± 19.52 seconds WT vs 97.38 ± 8.51 seconds SAPAP3−/−, t (17.88) = 2.58, P = 0.019)”

SAPAP3−/− exhibited decreased movement during EPM testing.

“During EPM testing, SAPAP3−/− exhibited decreased movement (Figure 3F: 4008.17 ± 156.34 cm WT vs 2292.15 ± 259.57 cm SAPAP3−/−, t (29)=5.36, P < 0.0001)”

SAPAP3−/− showed increased grooming duration during EPM testing compared to WT.

“Similar to the OF test, SAPAP3−/− showed increased grooming duration (Figure 2C: 35 ± 3.78 seconds WT vs 85.53 ± 13.23 seconds SAPAP3−/−, t (29)= − 3.37, P = 0.002) during EPM testing.”

In WT, the number of initiated trials did not change significantly with reversal or session.

“After exclusion of inactive sessions, the number of initiated trials for WT showed no significant effect of reversal (F (1,569.59) = 2.14, NS), nor an effect of session (F (35,30.3) = 0.73, NS) nor an interaction effect (F (35,30.3) = 1.01, NS) (Figure 3K).”

SAPAP3−/− showed decreased movement in the open field during both pre- and post-autoshaping sessions compared to WT.

“Post‐hoc analyses showed that SAPAP3−/− showed decreased movement during preautoshaping OF (Figure 3C: 21081.5 ± 4001 cm WT vs 10 644.6 ± 769.1 cm SAPAP3−/−, U = 38, z = −3.22, P = 0.001) and postautoshaping OF (Figure 3C: 21772.6 ± 2083.3 cm WT vs 12 445.2 ± 961 cm SAPAP3−/−, U = 18, z = −4.01, P < 0.0001).”

SAPAP3−/− showed decreased movement in the inner and outer zones of the open field.

“In addition, analyzing movement in the inner (data not shown, t(29)=2.15, P = 0.04) and outer diameter (data not shown, t(29)=2.24, P = 0.03) of the OF also showed that SAPAP3−/− showed decreased movement.”

Grooming during EPM testing was not significantly correlated with EPM performance.

“In addition, no correlation was found between grooming during EPM testing and EPM performance (ratio of time spent in closed vs open arms) (Pearson R 2 of 0.004; NS; 95% CI −0.43 to 0.53) (Figure 2F).”

SAPAP3−/− spent more time in closed arms on the EPM compared to WT.

“and more time in closed arms compared to WT (Figure 2B: 374.58 ± 24.27 seconds WT vs 445.28 ± 12.96 seconds SAPAP3−/−, t (20.14) =−2.57, P = 0.036).”

In SAPAP3−/−, preautoshaping and postautoshaping grooming durations were significantly correlated, indicating relatively consistent grooming over 3 months.

“A significant correlation was found between preautoshaping and postautoshaping grooming for SAPAP3−/− (Pearson R 2 of 0.243; P = 0.04; 95% CI 0.02‐0.79), indicating relatively consistent grooming over time (3 months) (Figure 2D).”

There was no difference in the number of initiated trials between WT and SAPAP3−/−.

“Direct comparison of initiated trials between WT and SAPAP3−/− showed no difference (Figure 3M: 33.82 ± 2.39 trials WT vs 27.83 ± 2.01 trials SAPAP3−/−, t (21)=1.93, NS).”

SAPAP3−/− showed decreased movement per minute of non-grooming time in the open field pre- and post-autoshaping.

“Post‐hoc tests showed that SAPAP3−/− showed decreased movement per minute preautoshaping (Figure 3D: 368.45 ± 71.42 cm/min WT vs 194.29 ± 13.1 cm/min SAPAP3−/−, U = 46, z = −2.9, P = 0.003) and postautoshaping (Figure 3D: 377.05 ± 37.63 cm/min WT vs 224.51 ± 15.13 cm/min SAPAP3−/−, U = 19, z = −3.97, P < 0.0001).”

SAPAP3−/− showed decreased activity during autoshaping intertrial intervals compared to WT.

“During autoshaping, average total beam breaks during intertrial intervals (as a proxy for activity) were averaged across sessions. SAPAP3−/− showed decreased activity compared to WT (Figure 3G: 438.35 ± 57.82 breaks WT vs 206.44 ± 28.13 breaks SAPAP3−/−, t (21)=3.71, P = 0.001).”

Decreased activity in SAPAP3−/− was not an indirect consequence of spending more time grooming.

“This decreased activity was not an indirect consequence of SAPAP3−/− spending more time grooming instead of being active otherwise, because decreased activity remained, even after grooming periods were excluded from the analysis (ie, activity relative to time spent not grooming).”

WT sign tracking emerged during task acquisition.

“which emerged during task acquisition”

There was a significant main effect of reversal on maintenance (F(1,20)=11.38, P=0.003).

“A significant main effect of reversal on maintenance was found (F (1, 20) = 11.38, P = 0.003)”

There was a strong relationship between cue approach behavior during CS+ and difference score after reversal in WT (Pearson R2=0.75; P<0.0001; 95% CI 0.69-0.94).

“we tested the correlation between cue approach behavior during CS+ and difference score after reversal and found a strong relationship between these two measures (Pearson R 2 of 0.75; P < 0.0001; 95% CI 0.69‐0.94)”

There was no correlation between anxiety and postmaintenance difference score in SAPAP3−/− (Pearson R2=0.04; NS; 95% CI −0.72 to 0.45).

“or between anxiety and postmaintenance difference score Pearson R 2 of 0.04; NS; 95% CI −0.72 to 0.45)”

There was a significant main effect of genotype (F(1,20)=10.47, P=0.004).

“accompanied by a significant main effect of genotype (F (1, 20) = 10.47, P = 0.004)”

Grooming before and after autoshaping was correlated significantly.

“grooming before and after autoshaping was correlated significantly”

There was no significant difference between WT and SAPAP3−/− in premaintenance difference score before reversal (8.58±1.06 vs 5.98±0.75, t(21)=2.02, NS).

“post‐hoc analyses showed no significant difference between WT and SAPAP3−/− before reversal (Figure 5A bar graphs premaintenance: 8.58 ± 1.06 difference score WT vs 5.98 ± 0.75 difference score SAPAP3−/−, t (21) = 2.02, NS)”

Compulsive-like behavior, anxiety and behavioral inflexibility were unrelated.

“Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated.”

There was no correlation between increased grooming and anxiety in SAPAP3−/−.

“We then asked whether increased grooming and anxiety in SAPAP3−/− were related, but found no correlation between these two variables.”

Relative inactivity was not correlated with grooming itself.

“In addition, this relative inactivity was not correlated with grooming itself.”

Both genotypes ceased to goal-track after reversal.

“but ceased to goal‐track after reversal.”

There was no interaction effect between reversal and genotype (F(1,20)=0.51, NS).

“without an interaction effect (F (1, 20) = 0.51, NS)”

SAPAP3−/− were unable to adapt their behavior after contingency reversal.

“However, unlike WT, SAPAP3−/− were unable to adapt their behavior after contingency reversal, exemplified by a lack of re‐establishing CS+ approach behavior (sign tracking).”

SAPAP3−/− acquired Pavlovian approach behavior similarly to WT.

“SAPAP3−/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy.”

There was no correlation between grooming and premaintenance difference score in SAPAP3−/− (Pearson R2=0.004; NS; 95% CI −0.53 to 0.62).

“No correlation between grooming and premaintenance difference score was found (Pearson R 2 of 0.004; NS; 95% CI −0.53 to 0.62)”

Reward magazine approaches were not correlated with postmaintenance autoshaping performance.

“No correlation between reward magazine approaches and postmaintenance performance (E).”

SAPAP3−/− display increased grooming compared to WT, reflected in both number of grooming bouts and duration of grooming.

“Consistently, we confirm that SAPAP3−/− display increased grooming compared to WT, reflected in both number of grooming bouts and duration of grooming.”

There was no correlation between anxiety and premaintenance difference score in SAPAP3−/− (Pearson R2=0.08; NS; 95% CI −0.34 to 0.74).

“No correlation was found between anxiety and premaintenance difference score (Pearson R 2 of 0.08; NS; 95% CI −0.34 to 0.74)”

SAPAP3−/− were unable to adapt their conditioned approach behavior upon contingency reversal.

“but unlike WT, were unable to adapt their conditioned approach behavior upon contingency reversal.”

Average grooming in the open field was not correlated with postmaintenance autoshaping performance (difference score).

“No correlation between average grooming in the open field (OF) and postmaintenance autoshaping performance (difference score) (B).”

Both genotypes developed Pavlovian goal-tracking approaches during CS+ (reward-magazine approaches).

“Both genotypes developed Pavlovian “goal‐tracking” approaches during the CS+ (reward‐magazine approaches)”

SAPAP3−/− lacked re-establishing CS+ approach behavior (sign tracking) after reversal.

“However, unlike WT, SAPAP3−/− were unable to adapt their behavior after contingency reversal, exemplified by a lack of re‐establishing CS+ approach behavior (sign tracking).”

There was a significant difference between WT and SAPAP3−/− in postmaintenance difference score after reversal (6.31±0.69 vs 2.58±1.02, t(20)=3.03, P=0.028).

“a significant difference after reversal (Figure 5A bar graphs postmaintenance: 6.31 ± 0.69 difference score WT vs 2.58 ± 1.02 difference score SAPAP3−/−, t (20) = 3.03, P = 0.028) was found.”

SAPAP3−/− acquired responses to Pavlovian CS.

“We found that SAPAP3−/−, although less vigorous in their responses compared to WT, acquired responses to Pavlovian CS”

SAPAP3−/− show increased anxiety-like behavior on the EPM.

“We assessed anxiety on the EPM and confirmed previously reported augmentation of anxiety in SAPAP3−/−.”

• cites [7] Welch JM, Lu J, Rodriguiz RM, et al. Cortico‐striatal synaptic defects and OCD‐like behaviours in Sapap3‐mutant mice. Nature. 2007; 448: 894‐ 900. 17713528 PMC2442572 sourceNot checked yet

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WT exhibited sign tracking (CS+ approaches).

“WT exhibited “sign tracking” (CS+ approaches)”

In SAPAP3−/−, there was a significant interaction effect suggesting they approached CS+ and CS− differently before and after reversal.

“In SAPAP3−/−, we found a significant main effect of CS on autoshaping performance (F (1, 10) = 33.96, P < 0.0001), no main effect of reversal (F (1, 10) = 1.66, NS), but accompanied by a significant interaction effect (F (1, 10) = 9.81, P = 0.01), suggesting that SAPAP3−/− approached CS+ and CS− differently before and after reversal.”

Anxiety on the elevated plus maze was not correlated with postmaintenance autoshaping performance.

“No correlation between anxiety on the elevated plus maze (ratio of time spent closed/open arms) and postmaintenance performance (C).”

SAPAP3−/− acquired Pavlovian approach behavior less vigorously than WT.

“SAPAP3−/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy.”

WT sign tracking re-emerged towards the new CS+ after reversal.

“and re‐emerged towards the new CS+ after reversal”

CS approaches were strongly correlated with postmaintenance autoshaping performance.

“Strong correlation between CS approaches and postmaintenance performance (D).”

The degree of anxiety measured on the EPM did not correlate with grooming on the EPM itself (grooming state during paradigm).

“the degree of anxiety measured on the EPM did neither correlate with grooming on the EPM itself (grooming state during paradigm)”

There was no correlation between reward magazine approach behavior during CS+ and difference score after reversal (Pearson R2=0.02; NS; 95% CI −0.53 to 0.30).

“No correlation was found between reward magazine approach behavior during CS+ and difference score after reversal (Pearson R 2 of 0.02; NS; 95% CI −0.53 to 0.30)”

General activity (locomotion plus overall movement) was diminished in SAPAP3−/− compared to WT.

“General activity (ie, locomotion plus overall movement) was diminished compared to WT.”

The degree of anxiety measured on the EPM did not correlate with grooming repeatedly assessed in the OF (grooming trait over time).

“nor with grooming repeatedly assessed in the OF (grooming trait over time).”

SAPAP3−/− acquired Pavlovian approach behavior with a different strategy than WT.

“SAPAP3−/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy.”

There was no correlation between grooming and postmaintenance difference score in SAPAP3−/− (Pearson R2=0.05; NS; 95% CI −0.44 to 0.73).

“nor between grooming and postmaintenance difference score (Pearson R 2 of 0.05; NS; 95% CI −0.44 to 0.73)”

WT and SAPAP3−/− showed similar acquisition rate (no genotype effect on difference score during acquisition).

“A main effect of reversal on acquisition (F (1, 21) = 96.37, P < 0.0001) was found, but no main effect of genotype (F (1, 21) = 0.04, NS), nor an interaction effect (F (1, 21)=0.001, NS), suggesting similar acquisition rate between WT and SAPAP3−/−.”

Individual traits of SAPAP3−/− measured here (anxiety, compulsivity, flexibility, vigor) were not linearly related to one another.

“However, individual traits of SAPAP3−/− measured here (anxiety, compulsivity, flexibility, vigor) were not linearly related to one another”

WT re-acquired approach behavior under reversed reward contingencies, exclusively towards the CS+.

“whereas WT re‐acquired approach behavior under the reversed reward contingencies, although exclusively towards the CS+”

There was no correlation between movement and anxiety-like behavior assessed on the EPM.

“although no correlation was found between movement and anxiety‐like behavior assessed on the EPM”

In anticipation of reward, WT approached both the CS location and the reward magazine equally during CS+ presentation.

“In anticipation of reward, WT approached both the CS location and the reward magazine equally during CS+ presentation”

SAPAP3−/− did not recover responding after reversal.

“SAPAP3−/− did not recover responding”

SAPAP3−/− were able to learn to discriminate between CS+ and CS− similar to WT.

“We show that SAPAP3−/− were able to learn to discriminate between environmental stimuli predicting reward (CS+) and no reward (CS−) similar to WT”

The lack of behavioral adaptation in SAPAP3−/− was robust and persisted for an extended period of training after contingency reversal.

“This lack of behavioral adaptation was robust and persisted for an extended period of training after contingency reversal.”

After reversal, both genotypes refrained from reward magazine approaches.

“Surprisingly, after reversal, both genotypes refrained from reward magazine approaches.”

Once SAPAP3−/− learned CS contingencies, they were unable to update their behavioral response upon reversal.

“We report that once SAPAP3−/− learned CS contingencies, they were unable to update their behavioral response upon reversal.”

SAPAP3−/− displayed Pavlovian conditioned approach responses during presentation of these stimuli.

“and displayed Pavlovian conditioned approach responses during presentation of these stimuli”

During initial acquisition (prior to reversal), SAPAP3−/− employed a different approach strategy than WT.

“However, already during initial acquisition (prior to reversal), SAPAP3−/− employed a different approach strategy than WT.”

In anticipation of reward, SAPAP3−/− only approached the magazine during CS+ presentation.

“whereas SAPAP3−/− only approached the magazine.”

The phenotype of SAPAP3−/− mice maps remarkably well onto symptoms of human OCD patients.

“However, the previously showed virtue of the SAPAP3−/− model lies outside of genetics: The phenotype of these mice maps remarkably well onto symptoms of human OCD patients.”

The persistence of maladaptive patterns of inflexible thoughts and behaviors in OCD suggests a lack of cognitive flexibility.

“The persistence of maladaptive patterns of inflexible thoughts and behaviors suggest a lack of cognitive flexibility,4 the ability to adapt behavior in response to changing situational requirements.”

• cites [4] Gruner P, Pittenger C. Cognitive inflexibility in obsessive‐compulsive disorder. Neuroscience. 2017; 345: 243‐ 255. 27491478 PMC5288350 sourceNot checked yet

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Deficits in reversal learning associated with altered recruitment of fronto-striatal circuitry have been observed more consistently in OCD patients.

“Notably, deficits in reversal learning associated with altered recruitment of fronto‐striatal circuitry have been observed more consistently.31, 32, 33, 34, 35”

• cites [31] Chamberlain SR, Menzies L, Hampshire A, et al. Orbitofrontal dysfunction in patients with obsessive‐compulsive disorder and their unaffected relatives. Science (80‐). 2008; 321: 421‐ 422. 18635808 sourceNot checked yet

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• cites [32] Remijnse PL, van den Heuvel OA, Nielen MMA, et al. Cognitive inflexibility in obsessive‐compulsive disorder and major depression is associated with distinct neural correlates. PLoS One. 2013; 8: e59600. 23637737 PMC3634812 sourceNot checked yet

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• cites [33] Ravizza SM, Carter CS. Shifting set about task switching: behavioral and neural evidence for distinct forms of cognitive flexibility. Neuropsychologia. 2008; 46: 2924‐ 2935. 18601941 PMC2553424 sourceNot checked yet

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SAPAP3−/− had more excluded autoshaping sessions due to low trial initiation than WT.

“Analyses on the number of excluded sessions showed a significant main effect of genotype (F (1, 23)=4.26, P = 0.05) and a main effect of reversal (F (1, 23)=7.94, P = 0.01), but no interaction (F (1, 23)=0.19, NS), suggesting that although reversal had an effect on trial initiation in both genotypes, SAPAP3−/− were more inactive in general.”

SAPAP3−/− mice display compulsive-like grooming.

“Similar to subtypes of OCD patients, SAPAP3−/− display compulsive‐like grooming that can be decreased by deep‐brain stimulation.15”

• cites [15] Pinhal CM, van den Boom BJG, Santana‐Kragelund F, et al. Differential effects of deep brain stimulation of the internal capsule and the striatum on excessive grooming in Sapap3 mutant mice. Biol Psychiatry. 2018; 84: 917‐ 925. 29954580 sourceNot checked yet

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SAPAP3−/− mice exhibit dysregulation of projections from cortex to striatum.

“For example, both OCD patients11, 12, 13, 14 and SAPAP3−/− 7, 8 exhibit dysregulation of projections from cortex to striatum.”

• cites [7] Welch JM, Lu J, Rodriguiz RM, et al. Cortico‐striatal synaptic defects and OCD‐like behaviours in Sapap3‐mutant mice. Nature. 2007; 448: 894‐ 900. 17713528 PMC2442572 sourceNot checked yet

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• cites [8] Wan Y, Ade KK, Caffall Z, et al. Circuit‐selective striatal synaptic dysfunction in the sapap3 knockout mouse model of obsessive‐compulsive disorder. Biol Psychiatry. 2014; 75: 623‐ 630. 23414593 PMC3687030 sourceNot checked yet

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Individual mice display a relatively reliable degree of grooming, even over a period of months.

“indicating that individual mice display a relatively reliable degree of grooming, even over a period of months.”

SAPAP3−/− display cognitive deficits.

“Thus, SAPAP3−/− not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3−/− as a suitable model for the study of OCD.”

The increased grooming is a stable phenotype that is not affected by behavioral testing.

“suggestive of a stable phenotype that is not affected by behavioral testing.”

The sign-tracking behavioral strategy contributed to successful reversal learning.

“suggesting that this behavioral strategy contributed to successful reversal learning.”

Compulsive behavior and anxiety are not causally related to one another in SAPAP3−/−.

“Therefore, our findings imply that compulsive behavior and anxiety are not causally related to one another in SAPAP3−/−”

SAPAP3−/− are capable of Pavlovian learning.

“This study shows that SAPAP3−/− are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior.”

CS+ approach behavior is involved in successful reversal learning.

“suggesting that CS+ approach behavior is involved in successful reversal learning.”

SAPAP3−/− lack flexibility to adapt associated conditioned approach behavior.

“This study shows that SAPAP3−/− are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior.”

The unrelatedness of compulsive-like behavior, anxiety and behavioral inflexibility suggests a non-causal relationship between these traits.

“The observation that compulsive‐like behavior, anxiety and behavioral inflexibility were unrelated suggests a non‐causal relationship between these traits and may be of clinical relevance for the treatment of OCD.”

SAPAP3−/− are a suitable model for the study of OCD.

“Thus, SAPAP3−/− not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3−/− as a suitable model for the study of OCD.”

Grooming and anxiety-like behavior have independent etiologies in SAPAP3−/−.

“suggesting that these traits have independent etiologies.”

A compromised PFC-striatal network present in SAPAP3−/− is possibly responsible for the lack of adaptation to changing situational requirements.

“Thus, a compromised PFC‐striatal network present in SAPAP3−/−, which was shown to be involved in their excessive grooming,7, 8, 15, 16 is possibly responsible for the lack of adaptation to changing situational requirements.”

• cites [7] Welch JM, Lu J, Rodriguiz RM, et al. Cortico‐striatal synaptic defects and OCD‐like behaviours in Sapap3‐mutant mice. Nature. 2007; 448: 894‐ 900. 17713528 PMC2442572 sourceNot checked yet

  Not checked in the free run.

• cites [8] Wan Y, Ade KK, Caffall Z, et al. Circuit‐selective striatal synaptic dysfunction in the sapap3 knockout mouse model of obsessive‐compulsive disorder. Biol Psychiatry. 2014; 75: 623‐ 630. 23414593 PMC3687030 sourceNot checked yet

  Not checked in the free run.

• cites [15] Pinhal CM, van den Boom BJG, Santana‐Kragelund F, et al. Differential effects of deep brain stimulation of the internal capsule and the striatum on excessive grooming in Sapap3 mutant mice. Biol Psychiatry. 2018; 84: 917‐ 925. 29954580 sourceNot checked yet

  Not checked in the free run.

There is no overall Pavlovian learning deficit in SAPAP3−/−.

“indicating no overall Pavlovian learning deficit.”

The work provides further support for the use of the SAPAP3−/− model to study OCD-like behavior and its underlying neurobiology.

“Thus, our work provides further support for the use of the SAPAP3−/− model to study OCD‐like behavior and its underlying neurobiology.”

Both the lack of model-free response strategies in SAPAP3−/− and their behavioral inflexibility may be a consequence of SAPAP3−/−-inherent PFC-striatal dysfunction.

“suggesting that both the lack of model‐free response strategies in SAPAP3−/− and their behavioral inflexibility may be a consequence of SAPAP3−/−‐inherent PFC‐striatal dysfunction.”

• cites [68] Yin HH, Knowlton BJ, Balleine BW. Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur J Neurosci. 2004; 19: 181‐ 189. 14750976 sourceNot checked yet

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These traits show at least partial independence.

“suggesting at least partial independence”

A recent neuroimaging study employing Pavlovian fear conditioning found that OCD patients failed to flexibly update fear responses after reversal, despite normal acquisition of fear conditioning.

“Moreover, a recent neuroimaging study employing Pavlovian fear conditioning found that OCD patients failed to flexibly update fear responses after reversal, despite normal acquisition of fear conditioning.70”

• cites [70] Apergis‐Schoute AM, Gillan CM, Fineberg NA, Fernandez‐Egea E, Sahakian BJ, Robbins TW. Neural basis of impaired safety signaling in obsessive compulsive disorder. Proc Natl Acad Sci. 2017; 114: 3216‐ 3221. 28265059 PMC5373407 sourceNot checked yet

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These traits map well onto OCD symptomology.

“thereby mapping well onto OCD symptomology.”

SAPAP3−/− have been shown to groom excessively to the point of removing fur and occasionally producing skin lesions.

“SAPAP3−/− have been shown to groom excessively to the point of removing fur and occasionally producing skin lesions.7”

• cites [7] Welch JM, Lu J, Rodriguiz RM, et al. Cortico‐striatal synaptic defects and OCD‐like behaviours in Sapap3‐mutant mice. Nature. 2007; 448: 894‐ 900. 17713528 PMC2442572 sourceNot checked yet

  Not checked in the free run.