Figure 9.
Proposed model for TNFα-induced downregulation of GABAergic neurotransmission at hippocampal synapses. Compared with normal conditions (left), conditions associated with elevated levels of TNFα (right) lead to diminished postsynaptic responses to GABA as a result of lower levels of synaptic GABAARs. Activation of TNFR1 signals through p38 MAPK, PI3K, and PP1, which in turn dephosphorylates β3 S408/409 to enhance GABAAR endocytosis. A reduction in synaptic GABAARs is followed by a reduction in gephyrin clustering. TNFα may also affect presynaptic function by reducing synaptic vesicle release probability at some synapses, without affecting GABA synthesis.