DRD2 conditional mutant mice were shown to be hypersensitive to amphetamine in the open field locomotion test, the mice showing an increase in locomotion, and suggesting an endogenous mechanism for sensitization of the dopaminergic system.

Macalester College

- Connection Between DRD2, Parvalbumin Interneurons, and Schizophrenia
- The Effect of DRD2 Deletion from Parvalbumin Interneurons on Behavior
- Prefrontal Cortex Endophenotypes as a Result of DRD2 Deletion
- Cortico-striatal Imbalance in DRD2 Mice Mutants
- Sensitivity to Amphetamine in DRD2 Mice Mutants
- Effect of Antipsychotics on Schizophrenic Behavioral Phenotypes in DRD2 Mouse Mutants


Deletion of Dopamine D₂ Receptors from Parvalbumin Interneurons in Mouse Causes Schizophrenia-like Phenotypes

Tomasella, Eugenia, et al. “Deletion of Dopamine D₂ Receptors from Parvalbumin Interneurons in Mouse Causes Schizophrenia-like Phenotypes.” *Proceedings of the National Academy of Sciences*, vol. 115, no. 13, 12 Feb. 2018, pp. 3476–3481., https://doi.org/10.1073/pnas.1719897115. 


Deletion of dopamine D₂ receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes

- Selective dopamine D₂ receptor deletion from parvalbumin interneurons in mice causes a dysregulated dopaminergic system - including impaired inhibitory activity in the ventral hippocampus - since the D₂ receptor is necessary to modulate pyramidal neuron activity. The modulation of these interneurons may prevent overall dopaminergic dysregulation
- Disrupted parvalbumin interneuron (PVI) function is thought to be an integral part of the pathophysiology of schizophrenia. PVIs drive cortical gamma oscillations, which are important for working memory and why such impairments are common in schizophrenia patients. They are also critical for proper excitatory/inhibitory balance in the brain.
- Inhibitory activity starts to be promoted by DRD2 in the PVI around the time of adulthood, which could explain why schizophrenia manifests itself at this particular life stage


Connection Between DRD2, Parvalbumin Interneurons, and Schizophrenia

- DRD2 conditional mutant mice (where DRD2 is deleted) show a range of endophenotypes associated with schizophrenia and had a limited or blunted pharmacological response to aripiprazole 
- Adult conditional mutant mice showed an significant increase in overall locomotor activity, an increase in anxiety or risk-taking behaviors (evidenced by an increased proportion of time spent in the open arms of the test maze and a decrease in the amount of marbles they buried), showed working memory impairments by alternating significantly less times between the arms of the maze, and were shown to unravel significantly less cotton to buid their nests (suggesting decreased motivation)
- Conditional mice mutants spent an equal amount of time with new and familiar stimuli - which indicates they were treating all objects as if they were new, indicative of memory impairments.

The Effect of DRD2 Deletion from Parvalbumin Interneurons on Behavior

- Dopamine signaling through DRD2 regulates the spine morphology of pyrmidal neurons, so when DRD2 was deleted there was a marked decrease in dendritic spine density
- Reduced glycogen synthase kinase 3ꞵ (Gsk3ꞵ) seen in schizophrenia patients - including DRD2 conditional mutant mice
- Reduced mRNA expression of GAD67 and PV proteins reduced in the prefrontal cortex of conditional mutant mice without a significant change in parvalbumin interneuron (PVI) density
- NMDA receptor subunit NR2B was significantly reduced in conditional DRD2 mutant mice
- Alpha band (8-12 Hz) oscillations regulate the amplitude of the gamma band (30-70 Hz), and this was increased in the prefrontal cortex of conditional DRD2 mutant mice


Prefrontal Cortex Endophenotypes as a Result of DRD2 Deletion

There was a significant increase in dopamine metabolites in the striatum of DRD2 conditional mutant mice. Also there was a significant decrease in both dopamine and its metabolites in the prefrontal cortex of DRD2 conditional mutant mice


Cortico-striatal Imbalance in DRD2 Mice Mutants

Sensitivity to Amphetamine in DRD2 Mice Mutants

- DRD2 agonist quinpirole didn’t change the level of excitatory afferant stimulation, but it did significantly decrease inhibitory afferant activity in DRD2 mutant mice. This generated an excitatory/inhibitory imbalance in response to afferant activation - causing an increase in this ratio, which may lead to an increase in the response of pyramidal neurons when afferant activity arrives.
- Total locomotion was reduced down to basal levels in both controls and DRD2 mutants when risperidone was used in combination with amphetamine or NMDAR antagonist MK-801, which suggests that risperidone antagonism on DRD2 may have prevented the effect of massively released dopamine and that DRD2 expression in parvalbumin interneurons wasn’t required by risperidone to lower locomotor activity
- When treated with aripiprazole in combination with amphetamine, controls saw a significant decrease in total locomotion but only a partial decrease in DRD2 conditional mutants
- When treated with aripiprazole in combination with MK-801, control mice saw a significant decrease in locomotion but DRD2 mutants were resistant to aripiprazole treatment - which indicates that DRD2 expression on parvalbumin interneurons is required by this particular antipsychotic to recover from induced hyperlocomotion. 

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