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

Department of Pharmacology, Columbia University, New York, New York, United States
Cell (Impact Factor: 32.24). 12/2004; 119(5):719-32. DOI: 10.1016/j.cell.2004.11.020
Source: PubMed


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.


Available from: Joshua T Dudman
  • Source
    • "As I H elevation seems to be detrimental for cortical integrity and cognition, while I H inhibition in PFC by HCN channel blockade or HCN1 channel knockdown improves cognitive performance [52,103,113]. I H reduction would result in significant enhancement of local recurrent network activity in cortical networks, presumably through enhanced effectiveness of dendritic synaptic potentials to initiate action potential activity [103,113,114], seeFig. 1. "
    [Show abstract] [Hide abstract] ABSTRACT: In this review we describe how highly addictive psychostimulants such as cocaine and methamphetamine actions might underlie hypoexcitabilty in frontal cortical areas observed in clinical and preclinical models of psychostimulant abuse. We discuss new mechanisms that describe how increments on synaptic dopamine release are linked to reduce calcium influx in both pre and postsynaptic compartments on medial PFC networks, therefore modulating synaptic integration and information. Sustained DA neuromodulation by addictive psychostimulants can “lock” frontal cortical networks in deficient states. On the other hand, other psychostimulants such as modafinil and methylphenidate are considered pharmacological neuroenhancement agents that are popular among healthy people seeking neuroenhancement. More clinical and preclinical research is needed to further clarify mechanisms of actions and physiological effects of cognitive enhancers which show an opposite pattern compared to chronic effect of addictive psychostimulants: they appear to increase cortical excitability. In conclusion, studies summarized here suggest that there is frontal cortex hypoactivity and deficient inhibitory control in drug-addicted individuals. Thus, additional research on physiological effects of cognitive enhancers like modafinil and methylphenidate seems necessary in order to expand current knowledge on mechanisms behind their therapeutic role in the treatment of addiction and other neuropsychiatric disorders.
    Full-text · Article · Jan 2016 · Pharmacological Research
    • "This is consistent with previous work in other brain regions (Castro-Alamancos et al., 2007; Tohidi and Nadim, 2009; Wang et al., 2006). However, how the membrane resonance modulates the network oscillation depends on the neural network connections and the different diseases (Marcelin et al., 2009; Moca et al., 2014; Nolan et al., 2004; Stark et al., 2013). Given that the STN receives both synaptic inhibitory input from the striatum and excitatory input from the cortex, it has long been considered as the central pacemaker in the BG (Plenz and Kital, 1999). "
    [Show abstract] [Hide abstract] ABSTRACT: The high-voltage spindles (HVSs), one of the characteristic oscillations that include theta frequencies in the basal ganglia (BG)-cortical system, are involved in immobile behavior and show increasing power in Parkinson’s disease (PD). Our previous results suggested that the D2 dopamine receptor might be involved in HVSs modulations in a rat model of PD. Membrane resonance is one of the cellular mechanisms of network oscillation; therefor, we investigated how dopamine modulates the theta frequency membrane resonance of neurons in the subthalamic nucleus (STN), a central pacemaker of BG, and whether such changes in STN neurons subsequently alter HVSs in the BG-cortical system. In particular, we tested whether dopamine modulates HVSs through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels-dependent membrane resonance in STN neurons. We found that an antagonist of D2 receptors, but not of D1 receptors, inhibited membrane resonance and HCN currents of STN neurons through a G-protein activity in acute brain slices. Our further in vivo experiments using local injection of a D2 receptor antagonist or an HCN blocker in STNs of free-moving rats showed an increase in HVSs power and correlation in the BG-cortical system. Local injection of lamotrigine, an HCN agonist, counteracted the effect induced by the D2 antagonist. Taken together, our results revealed a potential cellular mechanism underlying HVSs activity modulation in the BG-cortical system, i.e. tuning HCN activities in STN neurons through dopamine D2 receptors. Our findings might lead to a new direction in PD treatment by providing promising new drug targets for HVSs activity modulation.
    No preview · Article · Jan 2016 · Neuropharmacology
  • Source
    • "The hippocampus is reciprocally connected to the cerebral cortex, processing and storing information by means of synaptic plasticity mechanisms like long-term potentiation (LTP) and long-term depression (LTD) (Martin et al., 2000; Kemp and Manahan-Vaughan, 2004) entorhinal cortex (EC) projections constitute the main cortical pathways to the hippocampus through two distinct pathways: neurons in layer II of the EC project to dentate gyrus neurons, engaging a tri-synaptic circuit via CA3 neurons and then through the Schaffer fibers to CA1 neurons (Witter et al., 1988); a distinct pathway links neurons from layer III of the EC directly to the CA1 region via the temporoammonic (TA) pathway (Witter et al., 1988). Although both pathways are involved in the acquisition and storage of spatial information (Remondes and Schuman, 2002), their different functional roles are still unclear, in spite of different receptor composition and molecular underpinnings to induce synaptic plasticity present in the Schaffer fibers and the TA pathways (Magee, 1999; Nolan et al., 2004; Ahmed and Siegelbaum, 2009). Additionally, the two hippocampal pathways also seem to be differently fine-tuned by neuromodulation systems, as shown for the dopaminergic system (Otmakhova and Lisman, 2000). "
    [Show abstract] [Hide abstract] ABSTRACT: High sugar consumption is a risk factor for metabolic disturbances leading to memory impairment. Thus, rats subject to high sucrose intake (HSu) develop a metabolic syndrome and display memory deficits. We now investigated if these HSu-induced memory deficits were associated with metabolic and electrophysiological alterations in the hippocampus. Male Wistar rats were submitted for 9 weeks to a sucrose rich diet (35% sucrose solution) and subsequently to a battery of behavioural tests; after sacrifice, their hippocampi were collected for ex vivo high-resolution magic angle spinning (HRMAS) metabolic characterization and electrophysiological extracellular recordings in slices. HSu rats displayed a decreased memory performance (object displacement and novel object recognition tasks) and helpless behaviour (forced swimming test), without altered locomotion (open field). HRMAS analysis indicated a similar hippocampal metabolic profile of HSu and control rats. HSu rats also displayed no change of synaptic transmission and plasticity (long-term potentiation) in hippocampal Schaffer fibers-CA1 pyramid synapses, but had decreased amplitude of long-term depression in the temporoammonic (TA) pathway. Furthermore, HSu rats had an increased density of inhibitory adenosine A1 receptors (A1R), that translated into a greater potency of A1R in Schaffer fiber synapses, but not in the TA pathway, whereas the endogenous activation of A1R in HSu rats was preserved in the TA pathway but abolished in Schaffer fiber synapses. These results suggest that HSu triggers a hippocampal-dependent memory impairment that is not associated with altered hippocampal metabolism but is probably related to modified synaptic plasticity in hippocampal TA synapses.
    Full-text · Article · Dec 2015 · Neuroscience
Show more