Dopamine Receptor 1 Specific CRISPRa Mice Exhibit Disrupted Behaviors and Striatal Baseline Cellular Activity

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The striatum's D1-SPNs and A2A-SPNs play crucial roles in motor and reward behaviors.
• CRISPR-dCas9 systems offer cell-type specific gene expression control for studying these behaviors.
• Conditional transgenic Rosa26:LSL-dCas9-p300 mice enable Cre-driven dCas9-p300 expression.

Purpose of the Study:

• To generate and validate novel D1-SPN and A2A-SPN specific CRISPR-dCas9-p300 mouse lines.
• To investigate the baseline behavioral and electrophysiological characteristics of these new mouse lines.
• To assess the potential of these lines for elucidating striatal subtype-mediated behaviors.

Main Methods:

• Generation of Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 mouse lines by crossing Rosa26-LSL-dCas9-p300 with Drd1-Cre and Ador2a-Cre mice.
• Behavioral phenotyping including locomotion, repetitive behaviors, and reward learning assessments.
• Electrophysiological recordings of dorsal striatum D1-SPNs.

Main Results:

• Drd1-Cre:dCas9-p300 mice showed significant repetitive spinning, hyperlocomotion, and enhanced reward learning acquisition compared to controls.
• Ador2a-Cre:dCas9-p300 mice did not exhibit behavioral changes compared to littermates.
• Electrophysiology revealed increased excitatory drive in D1-SPNs of Drd1-Cre:dCas9-p300 mice.

Conclusions:

• The study underscores the importance of validating CRISPR-dCas9 mouse lines before experimental use.
• The Drd1-Cre:dCas9-p300 line is a valuable tool for investigating the molecular mechanisms of stereotypy and reward learning.
• Cell-type specific epigenomic manipulation provides insights into striatal neuron function.