Disruption of prepulse inhibition is associated with severity of compulsive behavior and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice

AbstractObsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.

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Rat Strain Differences in the Ability to Disrupt Sensorimotor Gating Are Limited to the Dopaminergic System, Specific to Prepulse Inhibition, and Unrelated to Changes in Startle Amplitude or Nucleus Accumbens Dopamine Receptor Sensitivity

Journal of Neuroscience ◽

10.1523/jneurosci.19-13-05644.1999 ◽

1999 ◽

Vol 19 (13) ◽

pp. 5644-5653 ◽

Cited By ~ 57

Author(s):

Gene G. Kinney ◽

Lynn O. Wilkinson ◽

Kay L. Saywell ◽

Mark D. Tricklebank

Keyword(s):

Nucleus Accumbens ◽

Dopamine Receptor ◽

Prepulse Inhibition ◽

Dopaminergic System ◽

Strain Differences ◽

Sensorimotor Gating ◽

Receptor Sensitivity ◽

Startle Amplitude ◽

Rat Strain

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Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700477114 ◽

2017 ◽

Vol 114 (19) ◽

pp. 5029-5034 ◽

Cited By ~ 45

Author(s):

Grietje Krabbe ◽

S. Sakura Minami ◽

Jon I. Etchegaray ◽

Praveen Taneja ◽

Biljana Djukic ◽

...

Keyword(s):

Nucleus Accumbens ◽

Frontotemporal Dementia ◽

Knockout Mice ◽

Nuclear Factor Κb ◽

Medium Spiny Neurons ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Spiny Neurons ◽

Increased Risk ◽

Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

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