Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice

Abstract

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection-specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age-independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e. slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

Reduced axon caliber in the associative striatum of theSapap3knockout mouse

“…Concretely, in this scenario, the observed reduction in axon caliber in a small cluster of striatal axons might arise from a population of cortico-striatal projection neurons. Given that axonal caliber is positively related to synaptic strength 42,43 , the here observed structural phenotype of a decrease of axon caliber in the associative striatum is in line with and corroborates a previously reported decrease in cortico-striatal synaptic strength in the associative striatum 30,32 . No such structural alterations were observed in cortical regions providing major input into the associative striatum, including lOFC and M2 30,32,52 .…”

“…Alternatively, the observed structural deviations in the associative striatum could arise from alterations in the striatal micro-circuitry, namely a diminished feed forward inhibitory network of striatal PV interneurons. A reduced axonal caliber arising specifically from the subpopulation of PV interneurons would be consistent with previously observed diminished cortico-striatal synaptic activity in general 58 , and with decreased numbers of PV interneurons specifically 28,32 . Altered striatal microcircuitry in form of a reduced inhibitory PV interneuronal network has been described both in patients with aberrant repetitive behaviors 38,39,63 as well as in the striatum of several mouse models 36,37,64 including the associative striatum of Sapap3-KO mice 28,32 .…”

“…Indeed, it has been demonstrated in primate motor callosal neurons that smaller axon diameter corresponds to smaller synaptic bouton size and consequent smaller neurotransmission release 58 . Hence, the reduced axon caliber in the associative striatum of Sapap3-KO mice further corroborates a connectivity deficit present in this region as previously suggested by other studies using in vitro electrophysiology 27,30,32,33 .…”

“…Currently, aberrant connectivity in the associative striatum, here observed as reduced axon caliber can be explained in two ways 27,30,32,33 . A first explanation is based on dysfunctional macrocircuitry of cortico-striatal loops.…”

“…The observed substantially increased input from M2 onto both MSNs and parvalbumin-positive (PV) interneurons in the centromedial striatum suggests an aberrant macrocircuitry involving, not only associative, but also sensorimotor cortico-striatal loops 30 . The implication not only of the associative but also sensorimotor corticostriatal loops is further supported by the finding of synaptic alterations in both circuits in young adult Sapap3-KO mice: cingulate area 1/M2 cortical projections to the dorsomedial striatum (DMS), and primary motor/M2 cortical projections to the dorsolateral striatum (DLS) 32 . Indeed, the presence of a mixed nature of RBs and affected associative and sensorimotor circuits in the Sapap3-KO mice are in line with the clinical studies reporting comorbidity of tic-and compulsive-like symptoms in both OCD and TS patients [19][20][21][22] .…”