Abstract
Purpose: :
TrkB is the cognate receptor for BDNF. Both BDNF and TrkB are expressed in the inner retina of rodents. BDNF signaling has been implicated in the proper synaptic targeting and functional synapse formation by the GABAergic interneurons in spinal cord and cerebellum. We and others have shown that an over-expression of BDNF accelerates laminar refinement of mouse retinal ganglion cell dendrites while retina specific knockdown of TrkB expression retards this process (Liu et al., 2007). Here, we tested whether BDNF/TrkB signaling regulated the maturation and maintenance of inhibitory synapses.
Methods: :
We used a TrkB-F616A mouse carrying a phenylalanine-to-alanine mutation in the ATP binding pocket of TrkB, rendering it sensitive to 1NM-PP1 which blocks the kinase activity of the protein (Kaneko et al., 2008). We employed immuno-histochemistry, ERG and MEA recordings, to study the consequences of temporally controlled suppression of TrkB signaling in the retina.
Results: :
The number of gephyrin puncta, a marker for postsynaptic neurons at inhibitory synapses, was reduced in TrkB F616A mice fed with 1NM-PP1 from P0-P30 or P30-P50, suggesting a role of TrkB signaling in both inhibitory synapse formation and maintenance. 1NM-PP1 feeding of TrkB F616A mice disrurpted laminar localization of some GABAergic cells, viz. horizontal, TH and ChAT positive amacrine cells. Many GAD6 positive processes anomalously extended to OPL in the 1NM-PP1 fed TrkB F616A mice. Inactivation of TrkB does not affect either scotopic or photopic ERGs. However, a long latency ON-response was unmasked in many ganglion cells of 1NM-PP1 fed TrkB F616A mice. Few or no long latency ON responses was observed either in 1NM-PP1 fed WT mice or in control TrkB F616A mice. Similar long latency ON response was previously documented in the WT mice in presence of inhibitory (GABA, glycine) receptor blockers (Renteria et al., 2006). Thus, our results are consistent with TrkB inactivation reducing the efficacy of inhibition in the retina.
Conclusions: :
Inactivation of TrkB kinase activity can disrupt some GABA and glycine mediated inhibition, both during retinal development and after these pathways have matured.
Keywords: development • retinal connections, networks, circuitry • inhibitory receptors