Targeting Ion Channels to Distal Dendrites

Neurons are divided into functional compartments: the soma houses the DNA and transcriptional machinery, the axons conduct action potentials, presynaptic boutons transmit synaptic signals, and dendrites receive and integrate synaptic information. These functional differences are achieved by localizing different complements of proteins to these compartments; axons contain a high density of voltage-gated channels, presynaptic boutons house the machinery for synaptic vesicle-mediated neurotransmitter release, while dendrites contain ligand-gated and voltage-gated ion channels that generate and integrate postsynaptic responses. These primary compartments are further divided in some cell types, allowing the dendrite to expand its information processing power. For example, in CA1 pyramidal neurons of the hippocampus, a brain region crucial for memory formation, the apical dendrite is divided into a proximal and a distal compartment. These two dendritic compartments receive synaptic inputs from different sources and contain different proteins, making them functionally distinct. While many motifs and molecules have been identified that regulate the trafficking of proteins to axons versus dendrites, little is known about the mechanisms of protein targeting to compartments within a dendrite. We have investigated the regulation of protein composition of the distal dendritic compartment in the CA1 neurons. This distal compartment is enriched in specific ion channels, including the hyperpolarization-activated HCN1 cation channel, which we have focused on because of its striking distal localization and its importance in hippocampal function. Using dissociated and organotypic hippocampal culture systems, we show that HCN1 surface expression is activity dependent. However, the axons that innervate the distal compartment are not required for HCN1 localization. Our data suggest that while activity plays a role in HCN1 channel regulation, it is not sufficient for the distal dendritic targeting. We show that proper distal localization of HCN1 channels requires a non-cell autonomous factor. We provide evidence that the extracellular matrix protein reelin acts as this non-cell autonomous factor regulating ion channel composition of the distal dendrites. Blocking reelin signaling in organotypic culture results in reduction of HCN1 in the dendrites and distal HCN1 levels are reduced in reeler mice. In vivo viral knockdown of dab1, the intracellular signaling partner of reelin, leads to loss of HCN1 and other distally enriched ion channels specifically from the distal dendrites, but does not alter ion channel composition of the proximal dendritic compartment. Viral knockdown of dab1 increases a physiological indicator of HCN channels at the soma, indicating that some of HCN1 channels are redistributed. Blockade of src family kinases that are activated by reelin signaling likewise leads to a loss of distally enriched ion channels. These results define a novel role for reelin signaling in dendritic compartmentalization by regulating ion channel composition

SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.

The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo. SRGAP2A promotes synaptic maturation, and ultimately the synaptic accumulation of AMPA and GABAA receptors, by interacting with key components of both excitatory and inhibitory postsynaptic scaffolds, Homer and Gephyrin. Furthermore, SRGAP2A limits the density of both types of synapses via its Rac1-GAP activity. SRGAP2C inhibits all identified functions of SRGAP2A, protracting the maturation and increasing the density of excitatory and inhibitory synapses. Our results uncover a molecular mechanism coordinating critical features of synaptic development and suggest that human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance