Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Abstract

The endocannabinoid system modulates learning, memory, and neuroinflammatory processes, playing a key role in neurodegeneration, including Alzheimer’s disease (AD). Previous results in a rat lesion model of AD showed modulation of endocannabinoid receptor activity in the basalo-cortical pathway following a specific lesion of basal forebrain cholinergic neurons (BFCNs), indicating that the glial neuroinflammatory response accompanying the lesion is related to endocannabinoid signaling. In this study, 7 days after the lesion, decreased astrocyte and increased microglia immunoreactivities (GFAP and Iba-1) were observed, indicating microglia-mediated neuroinflammation. Using autoradiographic studies, the density and functional coupling to G-proteins of endocannabinoid receptor subtypes were studied in tissue sections from different brain areas where microglia density increased, using CB1 and CB2 selective agonists and antagonists. In the presence of the specific CB1 receptor antagonist, SR141716A, [3H]­CP55,940 binding (receptor density) was completely blocked in a dose-dependent manner, while the selective CB2 receptor antagonist, SR144528, inhibited binding to 25%, at best. [35S]­GTPγS autoradiography (receptor coupling to Gi/0-proteins) evoked by CP55,940 (CB1/CB2 agonist) and HU308 (more selective for CB2) was abolished by SR141716A in all areas, while SR144528 blocked up to 51.8% of the coupling to Gi/0-proteins evoked by CP55,940 restricted to the nucleus basalis magnocellularis. Together, these results demonstrate that there are increased microglia and decreased astrocyte immunoreactivities 1 week after a specific deletion of BFCNs, which projects to cortical areas, where the CB1 receptor coupling to Gi/0-proteins is upregulated. However, at the lesion site, the area with the highest neuroinflammatory response, there is also a limited contribution of CB2.

Cortical lipids containing choline mediate cannabinoid-induced cognitive improvement

“…Although we found post toxin injection an increase in the number of Iba1 positive cells (microglia) in the region containing the NBM 61 , the anti-inflammatory properties of WIN55,212-2 62,63 did not modify the number of microglia cells. Since there are multiple microglial phenotypes, it is difficult to perform an extensive analysis based on protein markers 64 .…”

Cell lipotypes localization in brain by mass spectrometry imaging

“…3). We demonstrated in previous studies using this type of lesion increased Iba-1 and decreased GFAP labelling at the toxin injection site 9 . Lipotype-based reconstruction imaging gave results comparable to immunofluorescence techniques (Extended Data Fig.…”

“…3). We demonstrated in previous studies using this type of lesion increased Iba-1 and decreased GFAP labelling at the toxin injection site 9 .…”

XIth Cajal Conference: New frontiers in neuron‐glial plasticity in health and disease

“…Likewise, Iker Bengoetxea de Tena , from Rafael Rodríguez‐Puertas' laboratory (University of the Basque Country, Spain), discussed the relevance of the degeneration of the basal forebrain cholinergic system in AD (Rodríguez‐Puertas et al, 1994). He suggested that cannabinoid treatments might have beneficial neuroprotective effects in this context, because the eCB system is affected in animal models of cholinergic impairment (Llorente‐Ovejero et al, 2017; Llorente‐Ovejero et al, 2022).…”