Dax A. Hoffman

K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons

Pyramidal neurons receive tens of thousands of synaptic inputs on their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. Surprisingly, there turns out to be a very high density of transient A-type potassium ion channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent initiation of an action potential in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce excitatory synaptic events. The channels act to prevent large, rapid dendritic depolarizations, thereby regulating orthograde and retrograde propagation of dendritic potentials.

Role of an A-type K+ conductance in the back-propagation of action potentials in the dendrites of hippocampal pyramidal neurons.

Action potentials elicited in the axon actively back-propagate into the dendritic tree. During this process their amplitudes can be modulated by internal and external factors. We used a compartmental model of a hippocampal CA1 pyramidal neuron to illustrate how this modulation could depend on (1) the properties of an A-type K+ conductance that is expressed at high density in hippocampal dendrites and (2) the relative timing of synaptic activation. The simulations suggest that the time relationship between pre- and postsynaptic activity could help regulate the amplitude of back-propagating action potentials, especially in the distal portion of the dendritic tree.

Regulation of Dendritic Excitability by Activity-Dependent Trafficking of the A-Type K+ Channel Subunit Kv4.2 in Hippocampal Neurons

Voltage-gated A-type K+ channel Kv4.2 subunits are highly expressed in the dendrites of hippocampal CA1 neurons. However, little is known about the subcellular distribution and trafficking of Kv4.2-containing channels. Here we provide evidence for activity-dependent trafficking of Kv4.2 in hippocampal spines and dendrites. Live imaging and electrophysiological recordings showed that Kv4.2 internalization is induced rapidly upon glutamate receptor stimulation. Kv4.2 internalization was clathrin mediated and required NMDA receptor activation and Ca2+ influx. In dissociated hippocampal neurons, mEPSC amplitude depended on functional Kv4.2 expression level and was enhanced by stimuli that induced Kv4.2 internalization. Long-term potentiation (LTP) induced by brief glycine application resulted in synaptic insertion of GluR1-containing AMPA receptors along with Kv4.2 internalization. We also found evidence of Kv4.2 internalization upon synaptically evoked LTP in CA1 neurons of hippocampal slice cultures. These results present an additional mechanism for synaptic integration and plasticity through the activity-dependent regulation of Kv4.2 channel surface expression.

Dendritic potassium channels in hippocampal pyramidal neurons

Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back‐propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non‐uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium‐dependent potassium current on action potential repolarization is progressively reduced in the first 150 μm of the apical dendrites, so that action potentials recorded farther than 200 μm from the soma have no fast after‐hyperpolarization and are wider than those in the soma. The peak amplitude of back‐propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A‐type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long‐term potentiation induced by pairing EPSPs and back‐propagating action potentials.

Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones

A‐type potassium channels regulate neuronal firing frequency and the back‐propagation of action potentials (APs) into dendrites of hippocampal CA1 pyramidal neurones. Recent molecular cloning studies have found several families of voltage‐gated K+ channel genes expressed in the mammalian brain. At present, information regarding the relationship between the protein products of these genes and the various neuronal functions performed by voltage‐gated K+ channels is lacking. Here we used a combination of molecular, electrophysiological and imaging techniques to show that one such gene, Kv4.2, controls AP half‐width, frequency‐dependent AP broadening and dendritic action potential propagation. Using a modified Sindbis virus, we expressed either the enhanced green fluorescence protein (EGFP)‐tagged Kv4.2 or an EGFP‐tagged dominant negative mutant of Kv4.2 (Kv4.2gW362F) in CA1 pyramidal neurones of organotypic slice cultures. Neurones expressing Kv4.2gW362F displayed broader action potentials with an increase in frequency‐dependent AP broadening during a train compared with control neurones. In addition, Ca2+ imaging of Kv4.2gW362F expressing dendrites revealed enhanced AP back‐propagation compared to control neurones. Conversely, neurones expressing an increased A‐type current through overexpression of Kv4.2 displayed narrower APs with less frequency dependent broadening and decreased dendritic propagation. These results point to Kv4.2 as the major contributor to the A‐current in hippocampal CA1 neurones and suggest a prominent role for Kv4.2 in regulating AP shape and dendritic signalling. As Ca2+ influx occurs primarily during AP repolarization, Kv4.2 activity can regulate cellular processes involving Ca2+‐dependent second messenger cascades such as gene expression and synaptic plasticity.

Neuregulin-1 Reverses Long-Term Potentiation at CA1 Hippocampal Synapses

Neuregulin-1 (NRG-1) has been identified genetically as a schizophrenia susceptibility gene, but its function in the adult brain is unknown. Here, we show that NRG-1β does not affect basal synaptic transmission but reverses long-term potentiation (LTP) at hippocampal Schaffer collateral→CA1 synapses in an activity- and time-dependent manner. Depotentiation by NRG-1β is blocked by two structurally distinct and selective ErbB receptor tyrosine kinase inhibitors. Moreover, ErbB receptor inhibition increases LTP at potentiated synapses and blocks LTP reversal by theta-pulse stimuli. NRG-1β selectively reduces AMPA, not NMDA, receptor EPSCs and has no effect on paired-pulse facilitation ratios. Live imaging of hippocampal neurons transfected with receptors fused to superecliptic green fluorescent protein, as well as quantitative analysis of native receptors, show that NRG-1β stimulates the internalization of surface glutamate receptor 1-containing AMPA receptors. This novel regulation of LTP by NRG-1 has important implications for the modulation of synaptic homeostasis and schizophrenia.

Regulation of back−propagating action potentials in hippocampal neurons

Protein kinase C has recently been shown to modulate the slow recovery from inactivation of Na+ channels in apical dendrites of hippocampal CA1 pyramidal neurons. Moreover, dendritic, A-type K+ channels have been found to be modulated by protein kinases A and C and by mitogen-activated protein kinase. The electrical signalling ability of these dendrites is thus highly regulated by a number of neurotransmitters and second-messenger systems.

Molecular dissection of hippocampal theta-burst pairing potentiation

Long-term potentiation (LTP) of synaptic efficacy in the hippocampus is frequently induced by tetanic stimulation of presynaptic afferents or by pairing low frequency stimulation with postsynaptic depolarization. Adult (P42) GluR-A−/− mice largely lack these forms of LTP. LTP in wt mice can also be induced by coincident pre- and postsynaptic action potentials, where an initial rapid component is expressed but a substantial fraction of the potentiation develops with a delayed time course. We report here that this stimulation protocol, delivered at theta frequency (5 Hz), induces LTP in GluR-A−/− mice in which the initial component is substantially reduced. The remaining GluR-A independent component differs from the initial component in that its expression develops over time after induction and its induction is differentially dependent on postsynaptic intracellular Ca2+ buffering. Thus, in adult mice, theta-burst pairing evokes two forms of synaptic potentiation that are induced simultaneously but whose expression levels vary inversely with time. The two components of synaptic potentiation could be relevant for different forms of information storage that are dependent on hippocampal synaptic transmission such as spatial reference and working memory.

Human endogenous retrovirus-K contributes to motor neuron disease

Human endogenous retrovirus-K is activated in the cortical neurons of patients with amyotrophic lateral sclerosis, and expression of the viral envelope protein in mouse brain reproduces the clinical and pathological phenotype of this disease. A viral endgame A large number of viral sequences are present in the human genome but remain silent. However, under pathological conditions, these viruses can get expressed. Li et al. now report that one such virus, human endogenous retrovirus-K, is expressed in neurons of a subpopulation of patients with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease. The envelope protein of this virus causes degeneration of neurons, and transgenic animals expressing this protein develop an ALS-like syndrome caused by nucleolar dysfunction in motor neurons. Reactivation of the virus is regulated by the transcription factor TDP-43. Thus, therapeutic approaches against this virus could potentially alter the course of the disease. The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis.

Dendritic ion channel trafficking and plasticity

Dendritic ion channels are essential for the regulation of intrinsic excitability as well as modulating the shape and integration of synaptic signals. Changes in dendritic channel function have been associated with many forms of synaptic plasticity. Recent evidence suggests that dendritic ion channel modulation and trafficking could contribute to plasticity-induced alterations in neuronal function. In this review we discuss our current knowledge of dendritic ion channel modulation and trafficking and their relationship to cellular and synaptic plasticity. We also consider the implications for neuronal function. We argue that to gain an insight into neuronal information processing it is essential to understand the regulation of dendritic ion channel expression and properties.