The microtubule-associated protein tau accumulates in Alzheimer’s and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mis-targeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.

Dendritic, backpropagating action potentials (bAPs) facilitate the induction of Hebbian long-term potentiation (LTP).

Shal-type (Kv4.x) K+ channels are expressed in a variety of tissue, with particularly high levels in the brain and heart. These channels are the primary subunits that contribute to transient, voltage-dependent K+ currents in the nervous system (A currents) and the heart (transient outward current). Recent studies have revealed an enormous degree of complexity in the regulation of these channels. In this review, we describe the surprisingly large number of ancillary subunits and scaffolding proteins that can interact with the primary subunits, resulting in alterations in channel trafficking and kinetic properties. Furthermore, we discuss posttranslational modification of Kv4.x channel function with an emphasis on the role of kinase modulation of these channels in regulating membrane properties. This concept is especially intriguing as Kv4.2 channels may integrate a variety of intracellular signaling cascades into a coordinated output that dynamically modulates membrane excitability. Finally, the pathophysiology that may arise from dysregulation of these channels is also reviewed.

We investigated mitogen-activated protein kinase (MAPK) modulation of dendritic, A-type K+ channels in CA1 pyramidal neurons in the hippocampus. Activation of cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) leads to an increase in the amplitude of backpropagating action potentials in distal dendrites through downregulation of transient K+ channels in CA1 pyramidal neurons in the hippocampus. We show here that both of these signaling pathways converge on extracellular-regulated kinases (ERK)-specific MAPK in mediating this reduction in dendritic K+ current, which is confirmed, in parallel, by biochemical assays using phosphospecific antibodies against the ppERK and pKv4.2. Furthermore, immunostaining indicates dendritic localization of ppERK and pKv4.2. Taken together, these results demonstrate that dendritic, A-type K+ channels are dually regulated by PKA and PKC through a common downstream pathway involving MAPK, and the modulation of these K+ channels may be accounted for by the phosphorylation of Kv4.2 subunits.

Patients with OLP in China usually present with distinctive clinical morphology and characteristic distribution and few may display lesions with a confusing array of forms mimicking other diseases. A long time follow up is of utmost importance to detect its malignant transformation.

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.

Calcium-calmodulin-dependent kinase II (CaMKII) has a long history of involvement in synaptic plasticity, yet little focus has been given to potassium channels as CaMKII targets despite their importance in repolarizing EPSPs and action potentials and regulating neuronal membrane excitability. We now show that Kv4.2 acts as a substrate for CaMKII in vitro and have identified CaMKII phosphorylation sites as Ser438 and Ser459. To test whether CaMKII phosphorylation of Kv4.2 affects channel biophysics, we expressed wild-type or mutant Kv4.2 and the K ϩ channel interacting protein, KChIP3, with or without a constitutively active form of CaMKII in Xenopus oocytes and measured the voltage dependence of activation and inactivation in each of these conditions. CaMKII phosphorylation had no effect on channel biophysical properties. However, we found that levels of Kv4.2 protein are increased with CaMKII phosphorylation in transfected COS cells, an effect attributable to direct channel phosphorylation based on site-directed mutagenesis studies. We also obtained corroborating physiological data showing increased surface A-type channel expression as revealed by increases in peak K ϩ current amplitudes with CaMKII phosphorylation. Furthermore, endogenous A-currents in hippocampal pyramidal neurons were increased in amplitude after introduction of constitutively active CaMKII, which results in a decrease in neuronal excitability in response to current injections. Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K ϩ channels.

To delineate the cellular mechanisms underlying the function of medial prefrontal cortex (mPFC) networks, it is critical to understand how synaptic inputs from various afferents are integrated and drive neuronal activity in this region. Using a newly developed slice preparation, we were able to identify a bundle of axons that contain extraneocortical fibers projecting to neurons in the prelimbic cortex. The anatomical origin and functional connectivity of the identified fiber bundle were probed by in vivo track tracing in combination with optic and whole-cell recordings of neurons in layers 2/3 and 5/6. We demonstrate that the identified bundle contains afferent fibers primarily from the ventral hippocampus but does not include contributions from the mediodorsal nucleus of the thalamus, amygdala, or lateral hypothalamus/medial forebrain bundle. Further, we provide evidence that activation of this fiber bundle results in patterned activity of neurons in the mPFC, which is distinct from that of laminar stimulation of either the deep layers 5/6 or the superficial layer 1. Evoked excitatory postsynaptic potentials are monosynaptic and glutamatergic and exhibit bidirectional changes in synaptic efficacy in response to physiologically relevant induction protocols. These data provide the necessary groundwork for the characterization of the hippocampal pathway projecting to the mPFC.