Synapses are constantly changing in the human brain, especially during key developmental time points and often in response to activity. The mechanisms by which synapse formation, disintegration and pruning are managed are still not entirely clear. Kimberly McAllister’s lab works on this topic, seeking to identify and characterize the molecules involved in synaptic regulation. Among the potential proteins involved in regulation is major histocompatability complex class I (MHCI), an immune molecule with a purported role in development.
A recent paper from Dr. McAllister’s lab explores the role of MHCI in cortical development. MHCI is present before, during, and after synaptogenesis. Interestingly, the total density of MHCI is relatively constant at 3, 8, and 14 cellular days in vitro (div), however, levels of MHCI at the cell surface (sMHCI) increase over time. At 3 and 8 div, MHCI density is greater at proximal dendrites and expressed at higher density in areas where the glutamatergic synapses are fewer. At 14 div, expression at proximal and distal dendrites is more similar, congruent with a time-specific role for MHCI.
Using both small interfering RNA (siRNA) to knockdown MHCI in cell cultures and genetic manipulation to knockout the knock out the ß2m subunit or MHCI in mice, the authors show that lack of MHCI increases synaptic density (Figure 2 and 3). To prove the converse is also true, the authors demonstrate that over expression of MHCI decreasedsboth glutamatergic and GABAergic synapses (Figure 4). Despite the fact that MHCI regulates synaptic density at both excitatory and inhibitory synapses, it affects the amplitude of mEPSCs exclusively, exerting no significant influence on the amplitude of mIPSCs (Figure 5e & 5f).
Perhaps the most important finding from the paper is that MHCI plays a role in activity-dependent synaptic regulation. The authors apply tetrodotoxin (TTX) to mimic a decrease in activity. In response to treatment with TTX, young cortical cultures show increased glutamatergic synapses and decreased density of sMHCI. The blockade of synaptic activity also serves to reverse the distribution of sMHCI compared to control conditions suggesting that MHCI localization may be influenced by synaptic activity. Under conditions of decreased activity, a greater percentage of sMHCI is distributed in the distal dendrites as compared to the proximal. Over expression of MHCI eliminates the effects of TTX blockade (Figure 7e) indicating that MHCI is at least in part responsible for mediating activity-dependent manipulation of synapses.
The work of Dr. McAllister and her lab sheds light on the role of immune proteins in the brain and in brain development and increases our understanding of synapse operation. A better understanding of how disrupted immune function could play a role in diseases of the synapse opens the door for new ways of thinking about disease prevention and treatment.
Please join us on Tuesday, November 27th at 4 pm in the CNCB auditorium for Kimberly McAllister’s talk, titled “Novel roles for immune molecules in brain development and disease”
Cailey Bromer is a first year student in the Neurosciences. Ph.D. program and is rotating with Dr. John Kelsoe
Glynn M.W., Elmer B.M., Garay P.A., Liu X.B., Needleman L.A., El-Sabeawy F. & McAllister A.K. (2011). MHCI negatively regulates synapse density during the establishment of cortical connections, Nature Neuroscience, 14 (4) 442-451. DOI: 10.1038/nn.2764