Distinct Functional and Anatomical Architecture of the Endocannabinoid System in the Auditory Brainstem

Abstract

Zhao Y, Rubio ME, Tzounopoulos T. Distinct functional and anatomical architecture of the endocannabinoid system in the auditory brainstem. J Neurophysiol 101: 2434 -2446, 2009. First published March 11, 2009 doi:10.1152/jn.00047.2009. Endocannabinoids (ECs) act as retrograde messengers that enable postsynaptic cells to regulate the strength of their synaptic inputs. Here, by using physiological and histological techniques, we showed that, unlike in other parts of the brain, excitatory inputs are more sensitive than inhibitory inputs to EC signaling in the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus. The principal cells of the DCN, fusiform cells, integrate acoustic signals through nonplastic synapses located in the deep layer with multimodal sensory signals carried by plastic parallel fibers in the molecular layer. Parallel fibers contact fusiform cells and inhibitory interneurons, the cartwheel cells, which in turn inhibit fusiform cells. Postsynaptic depolarization or pairing of postsynaptic potentials (PSPs) with action potentials (APs) induced EC-mediated modulation of excitatory inputs but did not affect inhibitory inputs. Quantitative electron microscopical studies showed that glutamatergic terminals express more cannabinoid 1 receptors (CB1Rs) than glycinergic terminals. Fusiform and cartwheel cells express diacylglycerol lipase ␣ and ␤ (DGL␣/␤), the two enzymes involved in the generation of the EC, 2-arachidonoyl-glycerol (2-AG). DGL␣ and DGL␤ are found in the spines of cartwheel but not fusiform cells indicating that the synthesis of ECs is more distant from parallel fiber synapses in fusiform than cartwheel cells. The differential localization and density of DGL␣/␤ and CB1Rs leads to cell-and input-specific EC signaling that favors activitydependent EC-mediated suppression at synapses between parallel fibers and cartwheel cell spines, thus leading to reduced feedforward inhibition in fusiform cells. We propose that EC signaling is a major modulator of the balance of excitation and inhibition in auditory circuits.

The effects of the synthetic cannabinoid receptor agonists, WIN55,212-2 and CP55,940, on salicylate-induced tinnitus in rats

“…Despite early autoradiographic studies suggesting that the cochlear nucleus had the lowest expression of CB 1 receptors of any brain region (Herkenham et al, 1991), CB 1 receptors have been demonstrated to exist in the cochlear nucleus in moderate densities (Tzounopoulos et al, 2007;Zhao et al, 2009;Zheng et al, 2007). Tzounopoulos et al (2007), using immunogold labelling, have shown that CB 1 receptors are localised at the parallel fibre/cartwheel cell and parallel fibre/fusiform cell synapses in the dorsal cochlear nucleus and that they regulate synaptic plasticity such as LTD. Zhao et al (2009) went on to show that fusiform and cartwheel cells also express the enzymes, diacylglycerol lipase a and b, that are necessary for the synthesis of the endocannabinoid, 2 arachodonyl-glycerol (2-AG), which has been implicated in the regulation of epileptiform activity in other brain regions (Ludanyi et al, 2008).…”

“…Tzounopoulos et al (2007), using immunogold labelling, have shown that CB 1 receptors are localised at the parallel fibre/cartwheel cell and parallel fibre/fusiform cell synapses in the dorsal cochlear nucleus and that they regulate synaptic plasticity such as LTD. Zhao et al (2009) went on to show that fusiform and cartwheel cells also express the enzymes, diacylglycerol lipase a and b, that are necessary for the synthesis of the endocannabinoid, 2 arachodonyl-glycerol (2-AG), which has been implicated in the regulation of epileptiform activity in other brain regions (Ludanyi et al, 2008). Therefore, from these studies there is reason to think that cannabinoid drugs could modulate epileptiform activity in the cochlear nucleus that might be associated with tinnitus.…”

“…However, there have been relatively few studies of CB 1 receptors in the central auditory pathways. Both CB 1 and CB 2 receptors have been identified in the cochlear nucleus (Baek et al, 2008;Gong et al, 2006;Tzounopoulos et al, 2007;Zhao et al, 2009;Zheng et al, 2007), and recent electrophysiological studies indicate that these CB 1 receptors are functional and contribute to the regulation of longterm depression (LTD) (Tzounopoulos et al, 2007;Zhao et al, 2009). In the only study to date of CB 1 receptors in relation to tinnitus, Zheng et al (2007) reported that CB 1 receptors were down-regulated in the ventral, but not the dorsal, cochlear nucleus in the salicylate animal model of tinnitus.…”

Diverse levels of an inwardly rectifying potassium conductance generate heterogeneous neuronal behavior in a population of dorsal cochlear nucleus pyramidal neurons

“…However, these two possibilities are not mutually exclusive. Moreover, given that fusiform cells exhibit multiple forms of activity-dependent synaptic plasticity (Doiron et al 2011;Fujino and Oertel 2003;Zhao et al 2009, we propose that K ir conductances are potential targets for activity-dependent, intrinsic plasticity. Future experiments examining the developmental profile and the activity dependence of K ir heterogeneity are expected to provide answers to these questions.…”

Stimulus-dependent changes in optical responses of the dorsal cochlear nucleus using voltage-sensitive dye

“…A second factor that could contribute to the more sluggish optical responses to parallel fiber activation is that the underlying signals may originate from glia and dendrites, whose subthreshold responses have slower time courses. Since parallel fibers exert synaptic effects on both cartwheel cells and fusiform cells (Waller et al 1996;Manis and Molitor 1996;Davis et al 1996;Fujino and Oertel 2003;Zhao et al 2009;Tzounopoulos et al 2004), some component of the optical response may have originated from dendrites of these two cell types as well as their neighboring glial cells (astrocytes). A third possibility is that a slower conduction velocity could be in part related to the use of anesthetic in vivo.…”