OCD-Like Behaviors Caused by a Neuropotentiating Transgene Targeted to Cortical and Limbic D1+ Neurons

Abstract

To study the behavioral role of neurons containing the D1 dopamine receptor (D1ϩ), we have used a genetic neurostimulatory approach. We generated transgenic mice that express an intracellular form of cholera toxin (CT), a neuropotentiating enzyme that chronically activates stimulatory G-protein (G s ) signal transduction and cAMP synthesis, under the control of the D1 promoter. Because the D1 promoter, like other CNSexpressed promoters, confers transgene expression that is regionally restricted to different D1ϩ CNS subsets in different transgenic lines, we observed distinct but related psychomotor disorders in different D1CT-expressing founders. In a D1CT line in which transgene expression was restricted to the following D1ϩ CNS regions-the piriform cortex layer II, layers II-III of somatosensory cortical areas, and the intercalated nucleus of the amygdala-D1CT mice showed normal CNS and D1ϩ neural architecture but increased cAMP content in whole extracts of the piriform and somatosensory cortex. These mice also exhibited a constellation of compulsive behavioral abnormalities that strongly resembled human cortical-limbic-induced compulsive disorders such as obsessive-compulsive disorder (OCD). These compulsive behaviors included episodes of perseverance or repetition of any and all normal behaviors, repetitive nonaggressive biting of siblings during grooming, and repetitive leaping. These results suggest that chronic potentiation of cortical and limbic D1ϩ neurons thought to induce glutamatergic output to the striatum causes behaviors reminiscent of those in human cortical-limbic-induced compulsive disorders.

A transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder circuitry

“…10,19 Animal models of cortical-limbic hyperactivityinduced OCD-like or TS-like behavior may be useful to predict the specific neuronal circuitry of such dis-orders, as well as to screen new potential therapeutic drugs for TS, OCD and TTM. We recently created such a model of OCD-like compulsive symptoms, the D1CT-7 transgenic mice, 20 using a neuropotentiating transgene that expresses the cAMP-elevating, stimulusevoked neurotransmission-increasing intracellular A1 subunit of cholera toxin 21 in only two small subsets of neurons in the adult CNS. 20 The first subset is dopamine D1 and serotonin 5-HT2a,c receptor co-expressing (D1/5-HT2+) glutamatergic pyramidal projection neurons in somatosensory/insular cortex layers II-III and piriform cortex layer II, 16,20,22 which are known to send lateral and descending projections that glutamatergically excite sensorimotor and orbitofrontal plus deeper-layer corticostriatal neurons' glutamate output.…”

“…We recently created such a model of OCD-like compulsive symptoms, the D1CT-7 transgenic mice, 20 using a neuropotentiating transgene that expresses the cAMP-elevating, stimulusevoked neurotransmission-increasing intracellular A1 subunit of cholera toxin 21 in only two small subsets of neurons in the adult CNS. 20 The first subset is dopamine D1 and serotonin 5-HT2a,c receptor co-expressing (D1/5-HT2+) glutamatergic pyramidal projection neurons in somatosensory/insular cortex layers II-III and piriform cortex layer II, 16,20,22 which are known to send lateral and descending projections that glutamatergically excite sensorimotor and orbitofrontal plus deeper-layer corticostriatal neurons' glutamate output. 20 The second subset is D1 + GABAergic interneurons in the intercalated nucleus (ICN) of the amygdala, which indirectly triggers amygdalar glutamate output and anxiety.…”

“…20 The first subset is dopamine D1 and serotonin 5-HT2a,c receptor co-expressing (D1/5-HT2+) glutamatergic pyramidal projection neurons in somatosensory/insular cortex layers II-III and piriform cortex layer II, 16,20,22 which are known to send lateral and descending projections that glutamatergically excite sensorimotor and orbitofrontal plus deeper-layer corticostriatal neurons' glutamate output. 20 The second subset is D1 + GABAergic interneurons in the intercalated nucleus (ICN) of the amygdala, which indirectly triggers amygdalar glutamate output and anxiety. 20 This chronic hyperactivation of some of the same orbitofrontal, somatosensory-sensorimotor, and limbic glutamatergic output neurons proposed to be hyperactive in OCD was shown to cause the D1CT-7 mice to engage in unique, OCD-like behaviors 20 that are distinct from drug-induced stereotypies or limbic seizure behaviors 23 and that, as in human OCD (and TS), are aggravated by stress.…”

“…20 The second subset is D1 + GABAergic interneurons in the intercalated nucleus (ICN) of the amygdala, which indirectly triggers amygdalar glutamate output and anxiety. 20 This chronic hyperactivation of some of the same orbitofrontal, somatosensory-sensorimotor, and limbic glutamatergic output neurons proposed to be hyperactive in OCD was shown to cause the D1CT-7 mice to engage in unique, OCD-like behaviors 20 that are distinct from drug-induced stereotypies or limbic seizure behaviors 23 and that, as in human OCD (and TS), are aggravated by stress. 24,25 These OCD compulsion-like abnormal behaviors of the D1CT-7 transgenic mice include episodes of generalized perseveration or repetition of all normal behaviors as in OCD, and non-aggressive hair and skinpulling and biting of others or themselves during grooming, as in OCD or OCD-related TTM.…”

Genetic animal models of Tourette syndrome: The long and winding road from lab to clinic

“…Considering, for instance, the paediatric neurological disease spinal muscular atrophy (SMA) [51][52][53], we note that the underlying neurodegenerative pathology can be fully reproduced in an animal because: firstly, the aetiology, which involves a deficiency of the survival of motor neurons (SMN) protein, is clearly defined [54]; secondly, the disease manifestations in mice are noticeable and quantifiable including decreased lifespan, motor neuron loss, atrophic muscle fibres as well as motor defects [55][56][57][58]; and, thirdly, such abnormalities can be relieved by therapies known to be effective in humans such as those that increase SMN levels [59][60][61][62]. In the era preceding TS gene discovery, the animal model that by far exhibited the greatest behavioural similarities to TS is the D1 receptor cholera toxin (D1CT-7) transgenic mouse [63,64]. This model has corticallimbic hyperactivity triggered through the [65,66], Slitrk1-null mice had no compulsive and/or tic-related behaviours, a result that was unexpected given that in addition to TS, SLITRK1 has also been linked to TTM [2,67], which like TS is believed to belong to the OCD spectrum.…”