BDNF impairment in the hippocampus is related to enhanced despair behavior in CB₁ knockout mice

Abstract

Stress can cause damage and atrophy of neurons in the hippocampus by deregulating the expression of neurotrophic factors that promote neuronal plasticity. The endocannabinoid system represents a physiological substrate involved in neuroprotection at both cellular and emotional levels. The lack of CB1 receptor alters neuronal plasticity and originates an anxiety‐like phenotype in mice. In the present study, CB1 knockout mice exhibited an augmented response to stress revealed by the increased despair behavior and corticosterone levels showed in the tail suspension test and decreased brain derived neurotrophic factor (BDNF) levels in the hippocampus. Interestingly, local administration of BDNF in the hippocampus reversed the increased despair behavior of CB1 knockout mice, confirming the crucial role played by BDNF on the emotional impairment of these mutants. The neurotrophic deficiency seems to be specific for BDNF as no differences were found in the levels of nerve growth factor and NT‐3, two additional neurotrophic factors. Moreover, BDNF impairment is not related to the activity of its specific tyrosine kinase receptor or the activity of the transcription factor cAMP responsive element binding. These results suggest that the lack of CB1 receptor originates an enhanced response to stress and deficiency in neuronal plasticity by decreasing BDNF levels in the hippocampus that lead to impairment in the responses to emotional disturbances.

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…CB 1 receptor activation is associated to changes in growth factor expression, and can regulate tyrosine kinase growth factor receptors by direct transactivation mechanisms. In the adult nervous system, CB 1 receptor expression is involved in the regulation of the levels of the neurotrophin brain-derived neurotrophic factor (BDNF), and thus CB 1 -deficient mice have reduced hippocampal BDNF levels under basal circumstances, which could explain some of the neuronal plasticity and emotional alterations shown in those animals [63][64][65]. Transactivation of growth factor receptors with tyrosine kinase activity (EGFR, Trk B and others) has been shown to be involved in some CB 1 receptor-mediated neurodevelopmental actions [52].…”

Interactions between Intracellular Domains as Key Determinants of the Quaternary Structure and Function of Receptor Heteromers

“…The generation of mice lacking CB 1 receptor has been described elsewhere (18,19). Mice were housed five per cage in a temperature-(21 Ϯ 1°C) and humidity-controlled (55 Ϯ 10%) room with a 12:12 h light/dark cycle (light between 08:00 and 20:00 h) with food and water ad libitum.…”

Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum

“…These composite actions are likely to mediate the neuroprotective effects of BDNF (Castrén, 2004;Lu et al, 2005;Hennigan et al, 2007), as well as its complex effects on cognition and mood Martinowich et al, 2007). Signaling through cannabinoid CB 1 receptors (CB 1 Rs) is also emerging as a critical determinant in neuroprotection (Martínez-Orgado et al, 2007;Galve-Roperh et al, 2008), learning and memory (Horder et al, 2009;Puighermanal et al, 2009), and emotional control (Aso et al, 2008;Juhasz et al, 2009;Moreira et al, 2009), raising the possibility that BDNF and CB 1 Rs interact to regulate multiple functions in the brain.…”

“…BDNF levels, in fact, are decreased in the brain of mice lacking CB 1 Rs (Aso et al, 2008), whereas activation of these receptors increases BDNF in rodents (Butovsky et al, 2005) and in humans (D'Souza et al, 2009). Furthermore, BDNF release triggered by CB 1 R stimulation mediates the neuroprotective effects of cannabinoids (Khaspekov et al, 2004).…”