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Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1 , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in ( i ) locomotor activity, ( ii ) stereotypy, and ( iii ) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1 -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D 1 receptor binding in the dorsal striatum of Slc1a1 -STOP mice. Slc1a1 -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1 /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1 -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors., Competing Interests: Conflict of interest statement: C.K. has received research funding from Forest. C.K.J. has received research funding from AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, and Seaside Therapeutics. J.V. has consulted or served on advisory boards for Roche, Novartis, and SynapDx and has received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, and Forest.

The claustrum is a telencephalic gray matter structure with various proposed functions, including sensory integration and attentional allocation. Underlying these concepts is the reciprocal connectivity of the claustrum with most, if not all, areas of the cortex. What remains to be elucidated to inform functional hypotheses further is whether a pattern exists in the strength of connectivity between a given cortical area and the claustrum. To this end, we performed a series of retrograde neuronal tract tracer injections into rat cortical areas along the cortical processing hierarchy, from primary sensory and motor to frontal cortices. We observed that the number of claustrocortical projections increased as a function of processing hierarchy; claustrum neurons projecting to primary sensory cortices were scant and restricted in distribution across the claustrum, whereas neurons projecting to the cingulate cortex were densely packed and more evenly distributed throughout the claustrum. This connectivity pattern suggests that the claustrum may preferentially subserve executive functions orchestrated by the cingulate cortex. J. Comp. Neurol. 525:1347-1362, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Dopamine (DA) in the medial prefrontal cortex (mPFC) has been implicated in the regulation of subcortical DA function. To further characterize the potential interaction between cortical and subcortical DA systems, the short- and long-term neurochemical consequences of 6-hydroxydopamine (6-OHDA) lesions of the mPFC of rats were investigated in the mPFC and in its subcortical target structures. 4 to 5, 10 to 12 and 32 to 36 days after infusion of 6-OHDA, DA was depleted to a larger extent than noradrenaline and serotonin. No lesion-induced changes of DA and its metabolites were detected in subcortical structures. These results show that prefrontal 6-OHDA lesions produce immediate and long lasting depletions of prefrontal monoamines, especially of DA, without increasing basal DA metabolism in the striatum and nucleus accumbens.

In Parkinson's disease the dopaminergic inhibition--mediated by DA2 receptors in the striatum--is reduced. Therefore glutamatergic excitation predominates in the antero-dorsal striatum. In turn the glutamatergic neurons of the subthalamic nucleus become disinhibited. Antagonists of the NMDA-subtype of glutamate receptors injected locally into the glutamatergically innervated nuclei or competitive and non-competitive NMDA-antagonists administered systemically, counteract parkinsonian symptoms in animals.