Trends in Neurosciences
ReviewSonic Hedgehog Signaling and Hippocampal Neuroplasticity
Section snippets
Hippocampal Plasticity and Vulnerability
The hippocampus (see Glossary) is of critical importance for learning and memory because inputs conveyed from multiple sensory association cortices converge on neurons in hippocampal circuits, resulting in the potentiation of activated synapses [1]. The neuronal circuits of the hippocampus exhibit remarkable adaptive structural and functional responses to environmental demands; new synapses form, existing synapses can be pruned, and new neurons are generated from neural progenitor cells (NPCs)
Shh Signal Transduction
The core sequence of molecular events that mediate Shh signal transduction include 7, 8: (i) binding of Shh to a plasma membrane receptor called Patched (Ptch); (ii) activation of a membrane G-protein-coupled receptor (GPCR)-like protein called Smoothened (Smo) that, in the absence of Shh, is tonically inhibited by Ptch; (iii) recruitment and/or activation of a downstream protein complex that remains to be fully understood, but likely includes the kinesin-like protein Costal2, a kinase called
Shh and Hippocampal Neurogenesis
The vigorous neurogenesis that generates all neurons of the cerebral cortex during embryonic development is influenced greatly by Shh signaling. Thus, selective knockout of Shh and Smo in the embryonic telencephalon resulted in reduced proliferation of NPCs, reduced neurogenesis, and abnormal positioning of neurons in the neocortex [13]. NPCs generated in the ventral hippocampus during late embryonic development migrate to the dorsal hippocampus postnatally, a process that may be regulated by
Regulation of Axon Elongation and Synaptic Plasticity
While studies of commissural axons demonstrated that Shh can act directly on axons to regulate their growth 24, 25, 26, recent findings suggest that the outgrowth of axons of embryonic rat hippocampal neurons is not affected directly by Shh. Instead, hippocampal neuron axon elongation was stimulated by the activation of Shh signaling in the dendrites [27]. Ptch and Smo are present in the somatodendritic compartment of growing hippocampal neurons, where local activation of Smo results in the
Shh Interactions with the Notch and BDNF Signaling Pathways
Shh can affect the responsiveness of NPCs and neurons to other signals in their cellular niches, such that a cell will respond qualitatively or quantitatively differently to a local cue, depending upon the location of that cell within a Shh concentration gradient. Prominent among the signals that regulate hippocampal neurogenesis and synaptic plasticity are Notch ligands and BDNF 36, 37. Notch is a transmembrane protein that transduces signals from cell surface-associated ligands, such as
Shh Signaling and Neurological Disorders
Genetic defects in Shh signaling and teratogens, such as cyclopamine, that selectively inhibit Shh signaling can cause severe developmental abnormalities in the nervous systems of animals and humans, including holoprosencephaly [47]. Alterations of Shh signaling may also contribute to other neurodevelopmental disorders. Down syndrome (DS) is a disorder caused by triplication of chromosome 21. Patients with DS exhibit impaired development of cognitive abilities and motor coordination skills, and
Concluding Remarks and Future Directions
The emerging findings described in this article suggest that Shh signaling has roles in the proliferation and differentiation of hippocampal NPCs into neurons. By regulating axon outgrowth, synaptogenesis, and synaptic plasticity, Shh may regulate the formation and adaptive plasticity of hippocampal neuronal circuits throughout life. Many questions regarding the functions of Shh in hippocampal cell plasticity in health and disease remain (see Outstanding Questions). Additional unexplored
Acknowledgments
This work was supported by the Intramural Research Programs of the National Institutes of Health/National Institute on Aging and the National Institutes of Health/National Institute on Deafness and Other Communication Disorders. The code for the Advanced Imaging Core is ZIC DC000081. We thank Kristen Alexander for help with the preparation of illustrations.
Glossary
- Axon
- a long process emanating from the cell body of a neuron and forming a presynaptic terminal with a postsynaptic neuron.
- Brain-derived neurotrophic factor (BDNF)
- a protein involved in neurogenesis, synaptic plasticity, and neuronal stress resistance
- Cyclopamine
- a chemical that inhibits sonic hedgehog signaling.
- Dentate gyrus
- a neuronal cell layer in the hippocampus where neurogenesis occurs and that has a key role in spatial learning and memory.
- Down syndrome (DS)
- a developmental disorder caused by
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