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Dopamine D4 receptor-deficient mice display cortical hyperexcitability
M Rubinstein1, C Cepeda, R S Hurst
1Instituto de Investigaciones en Ingenieria Genética y Biologia Molecular, Consejo Nacional de Investigaciones Cientificas y Técnicas and Departamento de Ciencias Biológicas, Universidad de Buenos Aires, Argentina. mrubins@dna.uba.ar
Summary
Mice lacking the dopamine D(4) receptor (D(4)R) show increased brain activity and altered glutamate signaling in the frontal cortex. These findings suggest D(4)R acts as an inhibitory modulator of glutamate in this key brain region.
Area of Science:
- Neuroscience
- Molecular Biology
- Neuropharmacology
Background:
- The dopamine D(4) receptor (D(4)R) is primarily found in the frontal cortex (FC), crucial for cognitive and emotional functions.
- Limited availability of selective D(4)R drugs has hindered research into its physiological roles.
Purpose of the Study:
- To investigate the physiological significance of D(4)R by characterizing mice genetically deficient in this receptor.
- To explore the role of D(4)R in modulating neuronal activity and glutamate transmission in the frontal cortex.
Main Methods:
- Electrophysiological recordings (current and voltage-clamp) in cortical pyramidal neurons from wild-type and D(4)R-deficient mice.
- Analysis of spontaneous synaptic activity and induced paroxysmal discharges.
- Assessment of nerve terminal glutamate density in the motor cortex.
Main Results:
- D(4)R-deficient mice exhibited increased frequency and duration of spontaneous synaptic activity and induced epileptiform discharges.
- Enhanced synaptic activity was also observed with a selective D(4)R antagonist.
- Reduced nerve terminal glutamate density was found in D(4)R-deficient mice.
Conclusions:
- The dopamine D(4) receptor functions as an inhibitory modulator of glutamate activity in the frontal cortex.
- These findings provide new insights into the role of D(4)R in regulating cortical excitability and neurotransmission.