Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations

Ortega-Álvaro, A.; Navarrete, Francisco; Aracil-Fernández, Auxiliadora; Navarro, Daniela; Berbel, Pere; Manzanares, Jorge

doi:10.1038/npp.2015.113

Cited by 6 publications

(3 citation statements)

References 51 publications

(57 reference statements)

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“…Startle responses and inhibition of startle responses after presentation of a non-startling pulse (prepulse) was measured in an animal acoustic startle response system (Harvard Apparatus) as described before 57 . Mice were habituated to a transparent plastic-restrainer and to the conditioning chamber without background noise twice for 8 min the day prior to the PPI test.…”

Section: Methodsmentioning

confidence: 99%

Abnormal wiring of CCK+ basket cells disrupts spatial information coding

et al. 2017

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The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 is required for the normal integration of CCK+/VGlut3+ basket cells into cortical circuits. The number of inhibitory synapses made by CCK+/VGlut3+ basket cells and the inhibitory drive they exert on pyramidal cells are severely reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminishes the power of theta oscillations during exploratory behavior, disrupts spatial coding by place cells, and causes selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding information in hippocampus.

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Section: Methodsmentioning

confidence: 99%

Abnormal wiring of CCK+ basket cells disrupts spatial information coding

et al. 2017

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“…Deficient eCB signaling may contribute to many schizophrenia-like features in mice. Ablation of the CB1 receptor produces schizophrenia-like deficits, including cognitive inflexibility [ 28 ], reduced PPI [ 29 ], and anxiety [ 30 ]. Social isolation stress suppresses PPI in rats and disrupts eCB signaling [ 24 ] with reduced 2AG levels in the prefrontal cortex (PFC) [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of tyrosine phosphatase PTP1B in pyramidal neurons impairs endocannabinoid signaling by tyrosine receptor kinase trkB and causes schizophrenia-like behaviors in mice

Qin

Zhang

Cruz

et al. 2020

Neuropsychopharmacol.

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Schizophrenia is a debilitating disorder affecting young adults displaying symptoms of cognitive impairment, anxiety, and early social isolation prior to episodes of auditory hallucinations. Cannabis use has been tied to schizophrenia-like symptoms, indicating that dysregulated endogenous cannabinoid signaling may be causally linked to schizophrenia. Previously, we reported that glutamatergic neuron-selective ablation of Lmo4 , an endogenous inhibitor of the tyrosine phosphatase PTP1B, impairs endocannabinoid (eCB) production from the metabotropic glutamate receptor mGluR5. These Lmo4 -deficient mice display anxiety-like behaviors that are alleviated by local shRNA knockdown or pharmacological inhibition of PTP1B that restores mGluR5-dependent eCB production in the amygdala. Here, we report that these Lmo4 -deficient mice also display schizophrenia-like behaviors: impaired working memory assessed in the Y maze and defective sensory gating by prepulse inhibition of the acoustic startle response. Modulation of inhibitory inputs onto layer 2/3 pyramidal neurons of the prefrontal cortex relies on eCB signaling from the brain-derived neurotrophic factor receptor trkB, rather than mGluR5, and this mechanism was defective in Lmo4 -deficient mice. Genetic ablation of PTP1B in the glutamatergic neurons lacking Lmo4 restored tyrosine phosphorylation of trkB, trkB-mediated eCB signaling, and ameliorated schizophrenia-like behaviors. Pharmacological inhibition of PTP1B with trodusquemine also restored trkB phosphorylation and improved schizophrenia-like behaviors by restoring eCB signaling, since the CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl- N -1-piperidinyl-1H-pyrazole-3-carboxamide blocked this effect. Thus, activation of PTP1B in pyramidal neurons contributes to schizophrenia-like behaviors in Lmo4 -deficient mice and genetic or pharmacological intervention targeting PTP1B ameliorates schizophrenia-related deficits.

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“…However, this model has not been validated, as sensorimotor gating, measured by prepulse inhibition (PPI), was not affected in these rats [ 70 , 71 ], indicating that the capsaicin-treated rats did not satisfy this most widely accepted criterion for an animal model of schizophrenia. Both the endocannabinoid and vanilloid systems have been implicated in schizophrenia [ 73 ], and PPI has been shown to be disrupted in cannabinoid CB 1 and CB 2 receptor-knockout mice [ 74 , 75 ]. However, the effect of TRPV1 knockout on sensorimotor gating has not been reported.…”

Section: Trpv1 Channels and Psychiatric Conditionsmentioning

confidence: 99%

TRPV1 Channels in the Central Nervous System as Drug Targets

Chahl

2024

Pharmaceuticals

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TRPV1 channels are polymodal cation channels located predominantly on primary afferent neurons that are activated by inflammatory mediators, capsaicin (the active component in chili peppers), and noxious heat. TRPV1 channel antagonists are potential new analgesic agents, but their development has been hindered by the finding that they also produce loss of thermal homeostasis and response to noxious heat. Results from recent studies of the TRPV1 channel indicate that it might be possible to develop TRPV1 channel antagonists that inhibit pain without affecting noxious heat sensation. TRPV1 channels are also present in the central nervous system (CNS) and have been implicated in learning, memory, and behaviour. TRPV1 channel modulators have been proposed to have possible therapeutic potential in the treatment of neurological and psychiatric conditions. However, further understanding of the role of TRPV1 channels in the CNS is required before therapeutic advances in the treatment of neuropsychiatric conditions with TRPV1 channel modulators can be made.

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Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations

Cited by 6 publications

References 51 publications

Abnormal wiring of CCK+ basket cells disrupts spatial information coding

Abnormal wiring of CCK+ basket cells disrupts spatial information coding

Activation of tyrosine phosphatase PTP1B in pyramidal neurons impairs endocannabinoid signaling by tyrosine receptor kinase trkB and causes schizophrenia-like behaviors in mice

TRPV1 Channels in the Central Nervous System as Drug Targets

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