Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Abstract

Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are primarily unknown. In this study, we report that embryonic overexpression of neurotrophin-3 (NT3) in muscles disrupts the development of these specific Ia-MN connections, using transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic EPSPs evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.

Target selection of proprioceptive and motor axon synapses on neonatal V1‐derived Ia inhibitory interneurons and Renshaw cells

“…Postnatal modulation of synaptic strengths can result in significant circuit alterations. Disproportionate postnatal strengthening of Ia afferent central synapses, because of excessive supply of peripheral neurotrophin 3 (NT3), can overwhelm initial connectivity patterns and result in loss of specificity in the connections with motoneurons (Wang et al, 2007) or abnormal maintenance of high densities of VGLUT1 synapses on RCs (Mentis et al, 2010).…”

Multisensory Signaling Shapes Vestibulo-Motor Circuit Specificity

“…Egr3 mutant mice exhibit early postnatal degeneration of muscle spindles, leading to non-functional muscle spindle afferents (Chen et al, 2002;Tourtellotte and Milbrandt, 1998). In contrast, Mlc::NT3 mice overexpress NT3 from skeletal muscle fibers, resulting in survival of superfluous proprioceptive afferents with aberrant and more synaptic connections to central synaptic partners (Wang et al, 2007). To assess LVe input to motor neurons in these two mutant mouse strains compared to wildtype mice, we quantified synaptic input to motor neuron cell bodies and dendrites (Figures 7A and 7B).…”

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

“…Embryonic overexpression of NT3 in muscle of transgenic mice under the control of a myosin light chain-1 promoter leads to a substantial increase of monosynaptic excitatory postsynaptic potential (EPSP) amplitudes recorded extracellularly from ventral roots in neonatal mice (Wang et al 2007). Whereas the density of Ia projections to the ventral spinal cord appears unaltered, intracellular recordings from motoneurons show strong inputs from Ia afferents supplying unrelated muscles.…”