Cannabinoid Control of Learning and Memory through HCN Channels

Abstract

Summary The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP) and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Sublayer-Specific Coding Dynamics during Spatial Navigation and Learning in Hippocampal Area CA1

“…Superficial CA1 PCs exhibit more depolarized resting membrane potentials and larger h-current-mediated sag potentials in response to hyperpolarizing current pulses (Jarsky et al, 2008, Lee et al, 2014). Moreover, as recently reported (Maroso et al, 2016), superficial but not deep CA1 PCs exhibit a cannabinoid type-1 receptor (CB1R)-mediated regulation of h-currents.…”

“…Moreover, many of these differences are not randomly distributed throughout the hippocampus but rather are organized along its principal axes: dorsal-ventral (Fanselow and Dong, 2010; Jung et al, 1994; Kjelstrup et al, 2008, 2002; Maurer et al, 2005; Moser et al, 1993; Thompson et al, 2008), proximal-distal (Graves et al, 2012; Hartzell et al, 2013; Henriksen et al, 2010; Jarsky et al, 2008), and superficial-deep (Lee et al, 2014; Maroso et al, 2016; Mizuseki et al, 2011; Slomianka et al, 2011; Valero et al, 2015). The observed spatial organization of CA1 PC diversity is suggestive of regional specialization, whereby CA1 PCs along different axes could be biased in the information they process and in their contribution to different behaviors and forms of learning.…”

CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus

“…Indeed, differences in CA1PC morphology and intrinsic electrophysiological properties have been found along the radial axis (Fig. 2e) 42–44 , with distinct molecular regulatory mechanisms and downstream effects on learning and memory 45 . Moreover, much of this heterogeneity in the radial direction is expressed along with spatial gradients following the other principal axes of the hippocampus, the dorsoventral (reviewed in ref.…”

“…Bottom: examples of superficial CA1PC-biased signaling pathway, calcium-binding protein, and a divalent ion. H -current, a major regulator of dendritic excitability and synaptic input integration, is larger in superficial CA1PCs, and recent results indicate that tonic activity of postsynaptic cannabinoid type 1 receptors (CB1R) maintains the amplitude of I h through a dedicated molecular pathway 45 in these cells. HCN1, hyperpolarization-activated cyclic nucleotide-gated channel.…”

Heterogeneity in hippocampal place coding

“…However, it is also possible that differences in single-cell intrinsic biophysical properties and the genetic expression profiles that underlie such biophysics contribute. For example, a signaling pathway by which activation of cannabinoid type-1 receptors enhances the magnitude of the hyper-polarization activated cation current ( I h ) was recently reported to act exclusively in superficial, but not deep pyramidal cells [60]. I h , in turn, strongly impacts both long-term potentiation and the temporal summation of synaptic inputs [61].…”