Reorganizing Dendrites

Abstract

Newborn female rat pups have only about half the number of dendritic spines on their hypothalamic neurons as newborn male rat pups, a difference that disappears when the newborn females are treated with testosterone (which is aromatized to estradiol in the brain). Schwarz et al . found that estradiol treatment increased dendritic length and number of spines on neurons in the medial basal hypothalamus of newborn females to levels comparable to those in male pups and increased the abundance of the protein spinophilin. The glutamate agonist N -methyl-D-aspartate (NMDA) mimicked these effects, whereas NMDA- and AMPA-type glutamate receptor antagonists blocked the increase in spinophilin. Estradiol did not affect the abundance or the function of hypothalamic NMDA- and AMPA-type glutamate receptors. Rather, analysis of the ratio of the amplitudes of paired excitatory postsynaptic currents indicated that estradiol increased glutamate release from presynaptic neurons, as did experiments assessing depolarization- or electrical stimulation-dependent loss of the fluorescent dye FM4-54. Moreover, in vitro experiments indicated that stimulating glutamate release with α-latrotoxin also induced an increase in spinophilin. Estradiol’s stimulation of glutamate release did not depend on protein synthesis. Estradiol stimulated phosphorylation of the phosphatidylinositol 3-kinase (PI3K) substrate Akt and of extracellular signal-regulated kinase 1 and 2 [ERK 1/2, a target of MEK 1/2 (mitogen-activated or extracellular signal-regulated protein kinase kinase)]; timing and pharmacological analysis implicated PI3 kinase in the estradiol-dependent increase in glutamate release and indicated that ERK was phosphorylated downstream of glutamate receptor activation but upstream of the increase in spinophilin. In vitro experiments also implicated c-Jun N-terminal kinase (JNK) in the postsynaptic response. The authors conclude that the effects of estradiol on hypothalamic dendritic morphology are nongenomic and depend on PI3K activation and the consequent enhancement of presynaptic glutamate release. J. M. Schwarz, S.-L. Liang, S. M. Thompson, M. M. McCarthy, Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: A mechanism for organizational sex differences. Neuron 58 , 584-598 (2008). [PubMed]