Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord

Abstract

SUMMARY Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1ß on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…We therefore investigated the effect of genetic and pharmacological inhibition of p53 on motor neuron survival in SMA mice. For the genetic approach, we used a self-complementary adeno-associated virus serotype 9 (AAV9) expressing GFP and an shRNA against mouse p53, or GFP alone as a control (Figure S1A), delivered by intracerebroventricular injection (ICV) at P0 to transduce 60–80% of motor neurons (Figure S1B–C), (Mende et al, 2016; Passini et al, 2010). For pharmacological p53 inhibition, we administered pifithrin-α (PFT) by daily intra-peritoneal (IP) injections starting at P0 with a dose (2.2 mg/kg) known to suppress p53 transcriptional activity in vivo (Komarov, et al 1999, Murphy et al, 2004).…”

VGLUT1 synapses and P‐boutons on regenerating motoneurons after nerve crush

“…However, the well‐established downregulation of presynaptic inhibition in skin afferents after nerve injury (Castro‐Lopes et al, ; Horch & Lisney, ; Moore et al, ) prompted us to examine presynaptic inhibition of Ia afferents, which is known to effectively modulate the strength of the Ia‐motoneuron synapse and motor unit recruitment by Ia afferent inputs (Rudomin & Schmidt, ). The possibility that presynaptic inhibition to Ia afferents is altered after nerve injury was further suggested by a recent study concluding that the formation of presynaptic GABAergic inhibitory terminals (P‐boutons) and their strength modulating Ia afferent neurotransmission is regulated by activity‐dependent release of glutamate and brain derived neurotrophic factor from Ia synapses (Mende et al, ). In uninjured animals, Ia afferents maintain a continuous discharge that is modulated up‐or down according to muscle length, therefore, it is conceivable that disconnection of Ia afferents from muscle spindles causes diminished activity that could have dramatic effects on the maintenance of P‐boutons on Ia afferent synapses.…”

Insufficient developmental excitatory neuronal activity fails to foster establishment of normal levels of inhibitory neuronal activity

“…display inhibitory activity; this includes neurons that release the inhibitory neurotransmitter gamma aminobutyric acid ("GABAergic neurons"; Ben-Ari, 2002; Mende et al, 2016;Noh et al, 2010;Owens and Kriegstein, 2002;Takayama and Inoue, 2004). Culturing of neurons on multi-electrode arrays (MEAs) has provided insight into multiple aspects of neuronal function and development.…”