The role of neuroligin-3 and neuroligin-4 in synaptic transmission, long-term synaptic plasticity and excitation/inhibition balance in dentate granule cells
Final Report Abstract
The properties of excitatory and inhibitory transmission in dentate granule cells as well as their ability to undergo synaptic plasticity is the cellular basis for pattern separation and spatial learning and memory. Studies leading to this proposal have shown that neuroligins (NL1 and NL2) play important roles in this context. The central purpose of this DFG project was to better understand the role of NL3 and NL4 in synaptic function and plasticity in the hippocampal dentate gyrus. Our major focus was an in vivo and in vitro investigation of NL3 and NL4 KO animals. NL3 KO data: Our in vivo investigations showed that synaptic transmission evoked by stimulation of the perforant path was reduced in NL3 KO mice, but the coupling of the field excitatory postsynaptic potential (fEPSP) to the granule cell population spike was increased, indicating a compensatory increase in granule cell excitability. However, in contrast to mice lacking NL1, NL3 KO mice showed no impairments in stimulationinduced long-term potentiation (LTP) of these synapses. We observed a reduction in the expression levels of Nlgn1 and vesicular glutamate transporter 1 (VGlut1) in hippocampal synaptosomal preparations from Nlgn3 KO mice, which could partially explain the decrease in synaptic strength. We propose that the deletion of NL3 leads to a reduction in NL1-NL3 heterodimers, which regulate synaptic transmission, without affecting the NL1 homodimers, which regulate LTP. These results show that while NL1 and NL3 have distinct functions at the same synapse, their interactions may be equally important as their individual actions in determining the synaptic strength and could help explain the complex network disturbances in ASD patients with NL mutations. NL4 KO data: The statistical analysis of in vitro and in vivo electrophysiological data from NL4-deficient mouse lines is currently ongoing. Our unpublished preliminary data revealed that NL4 did not play a crucial role in non-Hebbian homeostatic synaptic plasticity (as measured in recordings of TTX-induced synaptic upscaling) in vitro or in Hebbian long-term plasticity (LTP) in vivo. Furthermore, our data indicated that neither excitatory nor inhibitory synaptic transmission nor E/I ratio was strongly affected by the NL4 deletion in dentate granule cells. The in vitro results were generally in line with in vivo findings. Moreover, using in vivo recordings of population spikes and their pairedpulse inhibition, we could provide first preliminary experimental evidence that NL4 KOs display reduced granule cell excitability. The cause for this diminished granule cell spiking remains to be determined but is unlikely to be linked to changes in E/I synaptic transmission ratio. Our data suggested that this effect was related to changes in nonsynaptic, presumably intrinsic granule cell properties. We plan to correlate our functional electrophysiological data with morphological data acquired from granule cell dendrite and spine imaging (work ongoing). The analysis of spine sizes and spine densities will complement our recordings of excitatory synaptic properties as its structural correlate.
Publications
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(2017) T2N as a new tool for robust electrophysiological modeling demonstrated for mature and adult-born dentate granule cells. eLife, 6, e26517
Beining M, Mongiat L, Schwarzacher SW, Cuntz H, Jedlicka P
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(2017) Synaptic plasticity and excitationinhibition balance in the dentate gyrus: Insights from in vivo recordings in neuroligin-1, -2 and collybistin knockouts. Neural Plasticity, 2018:6015753
Jedlicka P, Muellerleile J, Schwarzacher SW
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(2018) Structural homo- and heterosynaptic plasticity in mature and adult newborn rat hippocampal granule cells. PNAS, 115:E4670-E4679
Jungenitz T, Beining M, Radic T, Deller T, Cuntz H, Jedlicka P, Schwarzacher SWS
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(2019) Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo, Brain Structure and Function, 224:1279–1290
Vnencak M, Schwarzacher SW, Deller T, Willem M, Jedlicka P
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(2020) Enhanced LTP of population spikes in the dentate gyrus of mice haploinsufficient for neurobeachin. Scientific Reports,10:16058
Muellerleile J, Blistein A, Rohlmann A, Scheiwe F, Missler M, Schwarzacher SW, Jedlicka P
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(2020) Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1. The FASEB Journal, 34:2465-2482
Rudan Njavro J, … , Jedlicka P, Müller SA, Lichtenthaler SF
