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Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder
Published on: January 9, 2015
Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder
Yehong Wan1, Kristen K Ade1, Zachary Caffall1
1Department of Medicine, Division of Neurology, Durham, North Carolina.
Biological Psychiatry
|February 19, 2013
Summary
Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) deletion causes obsessive-compulsive disorder (OCD)-like behaviors by impairing corticostriatal, but not thalamostriatal, neurotransmission. SAPAP4 presence at thalamostriatal synapses explains this circuit-specific effect.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) is crucial for excitatory synaptic function and linked to obsessive-compulsive behaviors.
- Genetic deletion of Sapap3 in mice results in OCD-like behaviors, highlighting the role of striatal neurotransmission.
- Two major excitatory circuits in the striatum, corticostriatal and thalamostriatal, may be affected by neurotransmission defects.
Purpose of the Study:
- To investigate the circuit-level impact of Sapap3 deletion on synaptic transmission in the striatum.
- To determine whether corticostriatal or thalamostriatal circuits are responsible for OCD-like behaviors in Sapap3 knockout mice.
- To explore the molecular basis for potential functional differences between these striatal circuits.
Main Methods:
- Whole-cell electrophysiological recordings in acute brain slices of Sapap3 knockout and control mice.
- Utilizing transgenic fluorescent reporters to distinguish striatonigral and striatopallidal projection neurons.
- Employing immunostaining techniques to detect SAPAP isoform localization at synapses.
Main Results:
- Thalamostriatal synaptic activity remains unaffected in Sapap3 knockout mice.
- Corticostriatal synapses show reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor-mediated transmission following Sapap3 deletion.
- SAPAP4, a distinct SAPAP family member, is localized to thalamostriatal synapses but not corticostriatal synapses.
Conclusions:
- Sapap3 deletion primarily affects corticostriatal neurotransmission, implicating this circuit in the observed OCD-like behaviors.
- The differential localization of SAPAP isoforms (SAPAP3 and SAPAP4) to specific striatal circuits provides a molecular explanation for functional divergence.
- These findings elucidate circuit-level defects in an OCD mouse model and suggest circuit-selective principles governing SAPAP isoform localization.
