Circuit-Selective Striatal Synaptic Dysfunction in the Sapap3 Knockout Mouse Model of Obsessive-Compulsive Disorder

Abstract

Background SAP90/PSD-95-associated protein 3 (SAPAP3, also DLGAP3 or GKAP3) is an excitatory postsynaptic protein implicated in the pathogenesis of obsessive-compulsive behaviors. In mice, genetic deletion of Sapap3 causes obsessive-compulsive disorder (OCD)-like behaviors that are rescued by striatal expression of Sapap3, demonstrating the importance of striatal neurotransmission for the OCD-like behaviors. In the striatum, there are two main excitatory synaptic circuits, corticostriatal and thalamostriatal. Neurotransmission defects in either or both of these circuits could potentially contribute to the OCD-like behaviors of Sapap3 knockout (KO) mice. Previously we reported that Sapap3 deletion reduces corticostriatal AMPA-type glutamate receptor (AMPAR)-mediated synaptic transmission. Methods Whole-cell electrophysiological recording techniques in acute brain slices were used to measure synaptic transmission in the corticostriatal and thalamostriatal circuits of Sapap3 KO mice and littermate controls. Transgenic fluorescent reporters identified striatopallidal and striatonigral projection neurons. SAPAP isoforms at corticostriatal and thalamostriatal synapses were detected using immunostaining techniques. Results In contrast to corticostriatal synapses, thalamostriatal synaptic activity is unaffected by Sapap3 deletion. At the molecular level, we find that another SAPAP family member, SAPAP4, is present at thalamostriatal, but not corticostriatal synapses. This finding provides a molecular rationale for the functional divergence we observe between thalamic and cortical striatal circuits in Sapap3 KO mice. Conclusion These findings define the circuit-level neurotransmission defects in a genetic mouse model for OCD-related behaviors, focusing attention on the corticostriatal circuit for mediating the behavioral abnormalities. Our results also provide the first evidence that SAPAP isoforms may be localized to synapses according to circuit-selective principles.

Using mice to model Obsessive Compulsive Disorder: From genes to circuits

“…increased levels of NR2B and decreased levels of NR2A subunits). An additional study isolated these disturbances to cortico-striatal, rather than thalamo-striatal, synapses 91 . Though genetic investigation in a relatively small group of patients based on these results found no association of SAPAP3 SNPs with OCD, it did find associations in a subset of OCD patients with grooming disorders (e.g.…”

Tourette Syndrome: Bridging the Gap between Genetics and Biology

“…studied 289 TS trios, and determined a nominally significant genetic association between DLGAP3 and TS [118]. Moreover, DLGAP3/SAPAP3 KO mice have demonstrated OCD-like behaviors, such as compulsive grooming and anxiety, along with excitatory synaptic dysfunction in the striatum [119, 120]. …”

Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

“…The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) is located at the post-synaptic density of neuronal cells and it contributes to synaptic functioning. Such alterations might be linked to the synaptic functionality of this protein in excitatory synapses, particularly during glutamatergic synaptic transmission (Bresler et al, 2001;Wan et al, 2011Wan et al, , 2013Welch et al, 2004). In contrast, the gene encoding DLGAP2 (SAPAP2) has been associated with reduced OFC white matter volume in OCD (Wu et al, 2012); DLGAP2 status has not yet been studied as a risk factor for OCD.…”