Abstract
Neuronal activity is thought to drive the remodeling of circuits in the mammalian cerebral cortex. However, its precise function in the underlying formation and elimination of glutamatergic synapses has remained controversial. To clarify the role of activity in synapse turnover, we have assessed the effects of inhibition of glutamate release from a sparse subset of cultured hippocampal neurons on synapse turnover. Sustained chemogenetic attenuation of release through presynaptic expression of a designer receptor exclusively activated by designer drugs (DREADD) had no effect on the formation or elimination of glutamatergic synapses. Sparse expression of tetanus neurotoxin light chain (TeNT-LC), a synaptobrevin-cleaving protease that completely abolishes neurotransmitter release, likewise did not lead to changes in the rate of synapse elimination, although it reduced the rate of synapse formation. The stability of active and silenced synapses correlated with measures of synapse size. While not excluding a modulatory role in synapse elimination, our findings show that synaptic activity is neither required for the removal nor the maintenance of glutamatergic synapses between hippocampal neurons. Our results also demonstrate that the stability of glutamatergic synapses scales with their size irrespective of their activity.
Highlights
The mammalian brain has a much higher organizational complexity than any other biological tissue
We have characterized the formation and elimination of glutamatergic synapses using time-lapse imaging of hippocampal neurons in which pre- and post-synaptic structures were visualized with fluorescently tagged proteins
A recent in vivo study of spine dynamics in CA1 pyramidal neurons in the adult rodent hippocampus has reported rates of spine eliminations in the order of 40% over an observation period of 4 days (Pfeiffer et al, 2018). This degree of spine turnover far exceeds the morphological plasticity found in many regions of the neocortex and is likely due to intrinsic properties of hippocampal neurons (Attardo et al, 2015; Pfeiffer et al, 2018)
Summary
The mammalian brain has a much higher organizational complexity than any other biological tissue. Glutamate release may facilitate synapse formation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al, 1999; Richards et al, 2005; Kwon and Sabatini, 2011) or be required for the maintenance of glutamatergic synapses (McKinney et al, 1999; Yasuda et al, 2011). This notion is challenged, by findings that dendritic spine densities are essentially unaltered in neurons lacking ionotropic glutamate receptors (Lu et al, 2013) or in organotypic cultures of Munc131/2 knockout mice essentially devoid of neurotransmitter release (Sigler et al, 2017). We have re-investigated the role of glutamate release in synapse formation
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