Archive for the ‘THBS1’ Category
Posted in CACNA2D1, THBS1, THBS2, tagged CACNA2D1, Chemical synapse, Dendrite, Dendritic spine, Development, gabapentin, Neuron, neurontin, synaptogenesis, Voltage-dependent calcium channel on November 3, 2009| Leave a Comment »
If you compare the left panel to the right panel, you’ll see a dendrite (grey) with dendritic spines (green) on the left-side and then, on the right-side, these spines enveloped by the membrane of an astrocyte (white). These images were obtained from synapse-web.org who use a method known as 3D reconstruction of serial section electron microscopy – or something like that – to better understand what types of structural factors underlie normal and abnormal synaptic function. What is so amazing to me are the delicate ruffles of the astrocyte membrane that seem to want to ensheath each spine. Was any organelle so gently and well cared for? Perhaps not. These are dendritic spines afterall – the very structures that form synaptic contacts and process the neural signals – that allow us to think and function.
It turns out that astrocytes not only seem to care for dendritic spines, but also provide the essential signal that initiates the sprouting of neuronal spines in the first place. As covered in their recent paper, “Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis” [doi:10.1016/j.cell.2009.09.025] Eroglu and colleagues report the discovery – in mice – of CACNA2D1 the alpha-2/delta-1 subunit of the voltage-dependent calcium channel complex encodes a protein that binds to thrombospondins (humans have THBS1 and THBS2) which are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions – and are required for the formation of new dendritic spines. When neurons are cultured in the absence of thrombospondins, they fail to produce new spines and mice that do not make thrombospondins do not make very many excitatory synaptic spines.
The interesting twist to me is that thrombospondins are secreted solely by astrocytes! The newly identified CACNA2D1 receptor – as revealed by Eroglu et al., – binds to the EGF-repeats of thrombospondin and initiates a signalling cascade that results in the sprouting of new – silent – dendritic spines. Gabapentin, a drug that is prescribed for seizures, pain, methamphetamine addiction and many other mental health conditions appears to bind to CACNA2D1 and interfere with the binding of thrombospondin and also inhibits the formation of new spines in vitro as well during the development of somatotopic maps in the mouse whisker barrel cortex.
This seems to be an important discovery in the understanding of how cognitive development unfolds since much of the expression of thrombospondin and its effects on synaptogenesis occur in the early postnatal stages of development. I will follow this thread in the months to come.