Abstract
Maturation of neuronal and synaptic functions during early life is essential for the development of neuronal circuits and behaviors. In newborns synaptic transmission at excitatory synapses is primarily mediated by N-methyl-D-aspartate receptors (NMDARs), and NMDAR-mediated signaling plays an important role in synaptic maturation. Concomitant with synapse development, the intrinsic properties of neurons undergo dramatic changes during early life. However, little is known about the role of NMDARs in the development of intrinsic excitability. By using mosaic deletion of the obligatory GluN1 subunit of NMDARs in the thalamus of newborn mice, we showed that NMDARs regulate neuronal excitability during postnatal development. Compared with neighboring control neurons, neurons lacking NMDARs exhibit hyperexcitability and this effect is present throughout early life. Morphological analyses show that thalamic neurons without NMDARs have smaller soma size and fewer dendritic branches. Deletion of NMDARs causes a reduction of hyperpolarization-activated cation (HCN) channel function in thalamic neurons, and pharmacologically blocking HCN channels in wild type neurons mimics the effects of GluN1 deletion on intrinsic excitability. Deletion of GluN1 down-regulated mechanistic target of rapamycin (mTOR) signaling in thalamic neurons, and mosaic deletion of mTOR recapitulated the effects of GluN1 deletion. Our results demonstrate that NMDARs regulate intrinsic excitability and morphology of thalamic neurons through cell autonomous mechanisms that implicate mTOR signaling.
Highlights
Activation of N-methyl-D-aspartate receptors (NMDARs) by glutamate at excitatory synapses opens cation-selective channels with high permeability to Ca2+ ions and generates excitatory postsynaptic currents (EPSCs) with a slow time course
Neurons deficient of NMDARs showed a decrease in rheobase (Figure 3A) and an increase in the slope of the F-I curve (Figure 3B), together with an increase in input resistance (Figure 3C) and a decrease in whole-cell capacitance (Figure 3D). These effects are comparable to those observed at P14-16 and P20-21 (Figures 3A–D). These results suggest that NMDARs are required for postnatal development of intrinsic excitability in thalamic neurons
To determine whether hyperpolarization-activated cation (HCN) channels are implicated for the changes in intrinsic excitability in NMDAR-deficient neurons, we examined the effects of blocking HCN channels on excitability of VPm neurons in wild type (WT) mice
Summary
Activation of N-methyl-D-aspartate receptors (NMDARs) by glutamate at excitatory synapses opens cation-selective channels with high permeability to Ca2+ ions and generates excitatory postsynaptic currents (EPSCs) with a slow time course. In the brain of newborns, glutamatergic synapses contain few or no α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and synaptic transmission is mediated primarily by NMDARs (Isaac et al, 1995, 1997; Liao et al, 1995). Synaptic maturation is associated with an increase of AMPARs at the synapse, and this developmental change of AMPARs. NMDA Receptors Regulates Intrinsic Excitability is regulated by NMDARs (Liao et al, 1999; Adesnik et al, 2008; Zhang et al, 2013). NMDARs are required for pruning of redundant synaptic inputs during development (Ruthazer et al, 2003; Zhang et al, 2013). The role of NMDARs in the development of intrinsic excitability of neurons is poorly understood
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