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AMPA glutamate receptor subunits 1 and 2 regulate dendrite complexity and spine motility in neurons of the developing neocortex.

ABSTRACT: Within neurons of several regions of the CNS, mature dendrite architecture is attained via extensive reorganization of arbor during the developmental period. Since dendrite morphology determines the firing patterns of the neuron, morphological refinement of dendritic arbor may have important implications for mature network activity. In the neocortex, a region of brain that is sensitive to activity-dependent structural rearrangement of dendritic arbor, the proportion of AMPA receptors increases over the developmental period. However, it is unclear whether changes in AMPA receptor expression contribute to maturation of dendritic architecture. To determine the effects of increasing AMPA receptor expression on dendrite morphology and connectivity within the neocortex, and to determine whether these effects are dependent on specific AMPA receptor subunits, we overexpressed the AMPA glutamate receptor subunit 1 (GluR1) and glutamate receptor subunit 2 (GluR2) in cultured rat neocortical neurons at the time that AMPA receptors would normally be incorporated into synapses. Following expression of GluR1 or GluR2 we observed increases in the length and complexity of dendritic arbor of cortical neurons, and a concurrent reduction in motility of spines. In addition, expression of either subunit was associated with an increased density of excitatory postsynaptic puncta. These results suggest that AMPA receptor expression is an important determinant of dendrite morphology and connectivity in neocortical neurons, and further, that contrary to other regions of the CNS, the effects of AMPA receptors on dendrite morphology are not subunit-specific.

SUBMITTER: Chen W

PROVIDER: S-EPMC2647578 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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AMPA glutamate receptor subunits 1 and 2 regulate dendrite complexity and spine motility in neurons of the developing neocortex.

Chen W W Prithviraj R R Mahnke A H AH McGloin K E KE Tan J W JW Gooch A K AK Inglis F M FM

Neuroscience 20081207 1

Within neurons of several regions of the CNS, mature dendrite architecture is attained via extensive reorganization of arbor during the developmental period. Since dendrite morphology determines the firing patterns of the neuron, morphological refinement of dendritic arbor may have important implications for mature network activity. In the neocortex, a region of brain that is sensitive to activity-dependent structural rearrangement of dendritic arbor, the proportion of AMPA receptors increases o ...[more]

PMID: 19110036

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Project description:Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of the iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a degree of neuronal ID similar to that seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e. BdnfVI,Camk2a,Vamp1,Psd95,Cfl1, Pfn1,Pfn2, and Gda) and mitochondrial function (i.e. Ucp2,Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons were reduced. By 18DIV, partial recovery of the dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and the length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism, is responsible for the effects of fetal/neonatal ID and IDA on hippocampal neuron dendritic and synaptic maturation. Impairments in these neurodevelopmental processes likely underlie the negative impact of early life ID and IDA on hippocampus-mediated learning and memory.

Project description:Different families of auxiliary subunits regulate the function and trafficking of native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the central nervous system. While a facilitatory role of auxiliary subunits in ER export and forward trafficking of newly synthesized AMPA receptors is firmly established, it is unclear whether auxiliary subunits also control endosomal receptor turnover in dendrites. Here, we manipulated the composition of AMPA receptor complexes in cultured hippocampal neurons by overexpression of two auxiliary subunits, transmembrane AMPAR regulatory protein (TARP) γ-8 or cysteine knot AMPAR-modulating protein (CKAMP) 44a, and monitored dendritic receptor cycling in live-cell imaging experiments. Receptor surface delivery was assayed using a modified AMPA receptor subunit carrying the pH-dependent fluorophore superecliptic pHluorin (SEP-GluA1), which regains its fluorescence during receptor exocytosis, when transiting from the acidic lumen of transport organelles to the neutral extracellular medium. Strikingly, we observed a dramatic reduction in the spontaneous fusion rate of AMPA receptor-containing organelles in neurons overexpressing either type of auxiliary subunit. An analysis of intracellular receptor distribution also revealed a decreased receptor pool in dendritic recycling endosomes, suggesting that incorporation of TARPγ-8 or CKAMP44a in receptor complexes generally diminishes cycling through the endosomal compartment. To directly analyze dendritic receptor turnover, we also generated a new reporter by N-terminal fusion of a self-labeling HaloTag to an AMPA receptor subunit (HaloTag-GluA1), which allows for selective, irreversible staining of surface receptors. Pulse chase-experiments with HaloTag-GluA1 indeed demonstrated that overexpression of TARPγ-8 or CKAMP44a reduces the constitutive internalization rate of surface receptors at extrasynaptic but not synaptic sites. Thus, our data point to a yet unrecognized regulatory function of TARPγ-8 and CKAMP44a, by which these structurally unrelated auxiliary subunits delay local recycling and increase surface lifetime of extrasynaptic AMPA receptors.

Dataset Information

AMPA glutamate receptor subunits 1 and 2 regulate dendrite complexity and spine motility in neurons of the developing neocortex.

Publications

AMPA glutamate receptor subunits 1 and 2 regulate dendrite complexity and spine motility in neurons of the developing neocortex.

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