Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats.

Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10mg/kg, i.m.) and carisbamate (90mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury as characterized by Fluoro Jade C labeling was observed in critical brain areas including the dentate gyrus, parietal cortex, amygdala, and thalamus. Dantrolene and carisbamate treatment provided significant neuroprotection against delayed neuronal damage in these brain regions when administered one-hour after POX-SE. These results indicate that dantrolene or carisbamate could be effective adjuvant therapies to the existing countermeasures to reduce neuronal injury and behavioral morbidities post OP SE survival.

Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity.

Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

DISC1-dependent switch from progenitor proliferation to migration in the developing cortex.

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3ß, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.

Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.

Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming pathways or "signalosomes." Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and perinatal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.