Emerging roles for MEF2 transcription factors in memory.

In the brain, transcription factors are critical for linking external stimuli to protein production, enabling neurons and neuronal networks to adapt to the ever-changing landscape. Gene transcription and protein synthesis are also vital for the formation of long-term memory. Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors have a well-characterized role in the development of a variety of tissues, but their role in the adult brain is only beginning to be understood. Recent evidence indicates that MEF2 regulates the structural and synaptic plasticity underlying memory formation. However, in stark contrast to most other transcription factors implicated in memory, MEF2-mediated transcription constrains (rather than promotes) memory formation. Here, we review recent data examining the role of MEF2 in adult memory formation in rodents.

Activation of calcium/calmodulin-dependent protein kinase IIalpha in the striatum by the heteromeric D1-D2 dopamine receptor complex.

Synaptic plasticity in the striatum is a key mechanism that underlies processes such as reward related incentive learning and behavioral habit formation resulting from drugs of abuse. Key aspects of these functions are dependent on dopamine transmission as well as activation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha). In this study, we examined the ability of a recently identified heteromeric complex composed of D1 and D2 dopamine receptors coupled to Gq/11 to activate striatal CaMKIIalpha. Using the dopaminergic agonist SKF83959, which selectively activates the D1-D2 complex, we demonstrated phosphorylation of CaMKIIalpha at threonine 286, both in heterologous cells and in the murine striatum in vivo. Phosphorylation of CaMKIIalpha by activation of the receptor complex required concurrent agonism of both D1 and D2 receptors and was independent of receptor pathways that modulated adenylyl cyclase. The identification of this novel mechanism by which dopamine may modulate synaptic plasticity has implications for our understanding of striatal-mediated reward and motor function, as well as neuronal disorders in which striatal dopaminergic neurotransmission is involved.

Distribution and function of potassium channels in the electrosensory lateral line lobe of weakly electric apteronotid fish.

Potassium channels are one of the fundamental requirements for the generation of action potentials in the nervous system, and their characteristics shape the output of neurons in response to synaptic input. We review here the distribution and function of a high-threshold potassium channel (Kv3.3) in the electrosensory lateral line lobe of the weakly electric fish Apteronotus leptorhynchus, with particular focus on the pyramidal cells in this brain structure. These cells contain both high-threshold Kv3.3 channels, as well as low-threshold potassium channels of unknown molecular identity. Kv3.3 potassium channels regulate burst discharge in pyramidal cells and enable sustained high frequency firing through their ability to reduce an accumulation of low-threshold potassium current.

A prominent soma-dendritic distribution of Kv3.3 K+ channels in electrosensory and cerebellar neurons.

The expression pattern and subcellular distribution of a teleost homologue of the mammalian Kv3.3 potassium channel, AptKv3.3, was examined in the electrosensory lateral line lobe (ELL) and two cerebellar lobes in the hindbrain of the weakly electric gymnotiform Apteronotus leptorhynchus. AptKv3.3 expression was brain specific, with the highest level of expression in the cerebellum and 56% relative expression in the ELL. In situ hybridization revealed that AptKv3.3 mRNA was present in virtually all cell classes in the ELL as well as in the cerebellar lobes eminentia granularis pars posterior (EGp) and corpus cerebellum (CCb). Immunocytochemistry indicated a distribution of AptKv3.3 channels over the entire soma-dendritic axis of ELL pyramidal, granule, and polymorphic cells and over the soma and at least proximal dendrites (100 microm) of multipolar cells and neurons of the ventral molecular layer. AptKv3.3 immunolabel was present at the soma of cerebellar granule, golgi, eurydendroid, and CCb Purkinje cells, with an equally intense label throughout the dendrites of CCb Purkinje cells and EGp eurydendroid cells. Immunolabel was virtually absent in afferent or efferent axon tracts of the ELL but was detected on climbing fiber axons and on the axons and putative terminal boutons of CCb Purkinje cells. These data reveal a prominent soma-dendritic distribution of AptKv3.3 K+ channels in both principal output and local circuit neurons, a pattern that is distinct from the soma-axonal distribution that characterizes all other Kv3 K+ channels examined to date. The widespread distribution of AptKv3.3 immunolabel in electrosensory cells implies an important role in several aspects of signal processing.

The contribution of dendritic Kv3 K+ channels to burst threshold in a sensory neuron.

Voltage-gated ion channels localized to dendritic membranes can shape signal processing in central neurons. This study describes the distribution and functional role of a high voltage-activating K(+) channel in the electrosensory lobe (ELL) of an apteronotid weakly electric fish. We identify a homolog of the Kv3.3 K(+) channel, AptKv3.3, that exhibits a high density of mRNA expression and immunolabel that is distributed over the entire soma-dendritic axis of ELL pyramidal cells. The kinetics and pharmacology of native K(+) channels recorded in pyramidal cell somata and apical dendrites match those of AptKv3.3 channels expressed in a heterologous expression system. The functional role of AptKv3.3 channels was assessed using focal drug ejections in somatic and dendritic regions of an in vitro slice preparation. Local blockade of AptKv3.3 channels slows the repolarization of spikes in pyramidal cell somata as well as spikes backpropagating into apical dendrites. The resulting increase in dendritic spike duration lowers the threshold for a gamma-frequency burst discharge that is driven by inward current associated with backpropagating dendritic spikes. Thus, dendritic AptKv3.3 K(+) channels influence the threshold for a form of burst discharge that has an established role in feature extraction of sensory input.

Sequence diversity of voltage-gated potassium channels in an electric fish.

Cloning of voltage-gated K+ channels has indicated that these channels constitute a diverse family of genes that have been subclassified into four closely related gene families Kv1-Kv4 (Shaker, Shab, Shaw, Shal). A PCR approach has been used to assess the diversity of K+ channels in the weakly electric fish Apteronotus leptorhynchus, which is a well studied model of sensory processing. Degenerate primers specific for the highly conserved pore and S6 transmembrane domains of the K+ channel families were used to amplify an intronless 124 bp fragment from fish genomic DNA. DNA sequence analysis of a large number of these fragments has identified 19 putative K+ channels, each of which can be classified into one of the four major families. Ten fall into Kv1 class, two in the Kv2 class, five in the Kv3 class and two in the Kv4 class. The results indicate that the duplications that gave rise to multiple genes within each of the K+ channel families predate the divergence of the Actinopterygii and Sarcopterygii lineages (400 million years ago) during early vertebrate evolution.