Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC

Activation of prefrontal parvalbumin interneurons ameliorates treatment-resistant working memory deficit even under continuous antipsychotic treatment in a mouse model of schizophrenia

AbstractBACKGROUNDOne of the critical unmet medical needs in schizophrenia is a remedy for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. In addition, despite the patients with schizophrenia cannot stop taking antipsychotics due to a high rate of discontinuation-induced relapse, previous studies using animal models of schizophrenia have not considered these clinical situations.METHODSHere, we employ multi-dimensional approaches, including histological analysis in the prelimbic cortex, LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotic drugs, in vivo calcium imaging and behavioral analyses of mice using chemogenetic manipulation, to investigate neural mechanisms and potential therapeutic interventions for working memory deficit in a mouse model with chronic phencyclidine (PCP) administration that resembles the schizophrenia symptomatology.RESULTSChronic PCP administration led to abnormalities in excitatory and inhibitory synapses, including dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons, in layer 2–3 of the prelimbic cortex. Continuous olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not affect these synaptic abnormalities and working memory deficit in the PCP-treated mice. We found that the selective prelimbic PV activation, using hM3D(Gq)-DREADD system confirmed by in vivo calcium imaging, restored working memory deficit, even under continuous olanzapine treatment.CONCLUSIONSOur study raises a possibility that intervention in prefrontal PV neurons leads to an add-on therapy to antipsychotics targeting amelioration of treatment-resistant cognitive deficits in schizophrenia.</jats:sec

Methamphetamine increases locomotion and dopamine transporter activity in dopamine d5 receptor-deficient mice.

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors