NPP Seminar: Professor Zoltan Nusser, HUN-REN Institute of Experimental Medicine, Budapest, Hungary

Abstract: It has been known for decades that chemical synapses of the CNS show tremendous functional, and structural diversity.  Understanding the molecular mechanisms underlying functional synaptic diversity is a major challenge and has been the focus of our research in the past decades. One of the most intriguing examples of synaptic diversity is the so-called postsynaptic target cell type-dependent variations in the presynaptic glutamate release in cortical/hippocampal circuits.

The probability of glutamate release from hippocampal pyramidal cell (PC) axons that innervate oriens-lacunosum-moleculare (O-LM) interneurons is 10-fold lower than that innervating fast-spiking interneurons (FSINs). Pharmacological experiments demonstrated that the major difference between these two hippocampal synapses is their differential sensitivity to PDBU, indicating differential priming states of the SV. A sequential two-step priming model of synaptic transmission predicted a 6.5-fold smaller fraction of properly primed SVs at PC – O-LM synapses compared to those at PC – FSIN synapses, whereas the fusion probability of properly primed SVs is only 40% lower at PC – O-LM synapses. Using transgenic mice in which a single amino acid of Munc13-1 is mutated (H567K) we provide unequivocal evidence that the postsynaptic target cell type-dependent variability in presynaptic glutamate release in hippocampal network is the consequence of variability in SV priming, rather than differences in fusion of SVs.It has been known for decades that chemical synapses of the CNS show tremendous functional, and structural diversity. Understanding the molecular mechanisms underlying functional synaptic diversity is a major challenge and has been the focus of our research in the past decades.

One of the most intriguing examples of synaptic diversity is the so-called postsynaptic target cell type-dependent variations in the presynaptic glutamate release in cortical/hippocampal circuits. The probability of glutamate release from hippocampal pyramidal cell (PC) axons that innervate oriens-lacunosum-moleculare (O-LM) interneurons is 10-fold lower than that innervating fast-spiking interneurons (FSINs). Pharmacological experiments demonstrated that the major difference between these two hippocampal synapses is their differential sensitivity to PDBU, indicating differential priming states of the SV. A sequential two-step priming model of synaptic transmission predicted a 6.5-fold smaller fraction of properly primed SVs at PC – O-LM synapses compared to those at PC – FSIN synapses, whereas the fusion probability of properly primed SVs is only 40% lower at PC – O-LM synapses. Using transgenic mice in which a single amino acid of Munc13-1 is mutated (H567K) we provide unequivocal evidence that the postsynaptic target cell type-dependent variability in presynaptic glutamate release in hippocampal network is the consequence of variability in SV priming, rather than differences in fusion of SVs.

Academic Host: Angus Silver, NPP