A Behavioral Role for Dendritic IntegrationHCN1 Channels Constrain Spatial Memory and Plasticity at Inputs to Distal Dendrites of CA1 Pyramidal Neurons

Abstract

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells.

Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

“…Lack of HCN1 channels increases the dendritic input resistance in cortical neurons, leading to greater synaptic integration and firing (Huang et al, 2009). In the same HCN1-null mouse model, greater dendritic excitability and temporal summation was also observed in hippocampal CA1 pyramidal neurons (Nolan et al, 2004;Tsay et al, 2007). In agreement with a role for I h downregulation in epileptogenesis, HCN2-deficient mice generated by global Hcn2 knock-out exhibit spontaneous absence seizures (Ludwig et al, 2003).…”

Dendritic HCN2 Channels Constrain Glutamate-Driven Excitability in Reticular Thalamic Neurons

“…Consistently, dendritic I h current density and amplitude increases as one moves farther away from the soma (Magee, 1998;Williams and Stuart, 2000;Berger et al, 2001;Kole et al, 2006). Dendritic I h normalizes temporal summation (Stuart and Spruston, 1998;Magee, 1999;Berger et al, 2001;Koch and Grothe, 2003), disconnects somatic and dendritic spike initiation zones (Berger et al, 2003), and likely limits the development of long-term potentiation (Nolan et al, 2004).…”

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…Examination of HCN expression patterns, and the effects of gene deletion, reveals significant roles for some subunits expressed in the brain. For example, HCN1 regulates motor learning and spatial memory (Nolan et al, 2003(Nolan et al, , 2004, while HCN2 regulates thalamic excitability associated with absence seizures Ying et al, 2007b). The function of brain HCN3, however, has remained elusive (Herrmann et al, 2007).…”