Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner.

Felipe Espinosa,Shunan Liu,Zhong Xuan,Craig M Powell

doi:10.3389/fnsyn.2015.00011

Abstract

Together with its presynaptic partner Neurexin 1 (Nxn1), Neuroligin 1 (NL1) participates in synapse specification and synapse maintenance. We and others have shown that NL1 can also modulate glutamatergic synaptic function in the central nervous system of rodent models. These molecular/cellular changes can translate into altered animal behaviors that are thought to be analogous to symptomatology of neuropsychiatric disorders. For example, in dorsal striatum of NL1 deletion mice, we previously reported that the ratio N-methyl-D-aspartate receptor (NMDAR) mediated synaptic currents to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) mediated synaptic currents (NMDA/AMPA) is reduced in medium spiny neuron (MSNs). Importantly, this reduction in NMDA/AMPA ratio correlated with increased repetitive grooming. The striatum is the input nucleus of the basal ganglia (BG). Classical models of this circuitry imply that there are two principal pathways that render distinct and somewhat opposite striatal outputs critical to the function of these nuclei in modulating motor behavior. Thus, we set out to better characterize the effects of NL1 deletion on direct and indirect pathways of the dorsal striatum by genetically labeling MSNs participating in the direct and indirect pathways. We demonstrate that a decrease in NMDAR-mediated currents is limited to MSNs of the direct pathway. Furthermore, the decrease in NMDAR-mediated currents is largely due to a reduction in function of NMDARs containing the GluN2A subunit. In contrast, indirect pathway MSNs in NL1 knockout (KO) mice showed a reduction in the frequency of miniature excitatory neurotransmission not observed in the direct pathway. Thus, NL1 deletion differentially affects direct and indirect pathway MSNs in dorsal striatum. These findings have potential implications for striatal function in NL1 KO mice.

Highlights

IntroductionZahir et al, 2008; Glessner et al, 2009; Gratacòs et al, 2009; Millson et al, 2012; An et al, 2014), and may be involved in cognitive decline in the Alzheimer’s disease (Saura et al, 2011; Bie et al, 2014)
We recently demonstrated that reduced NMDA/AMPA ratio in glutamatergic projections onto striatal medium spiny neurons (MSNs) correlated with increased grooming in Neuroligin 1 (NL1) knockout (KO) mice (Blundell et al, 2010), a phenotype reversed by D-cycloserine, suggesting a relationship between a reduction in N-methyl-D-aspartate receptor (NMDAR) currents and grooming
Our findings suggest a decrease in NMDAR-mediated synaptic transmission in NL1 KO mice that is selective for DR1 MSNs

Summary

Introduction

Zahir et al, 2008; Glessner et al, 2009; Gratacòs et al, 2009; Millson et al, 2012; An et al, 2014), and may be involved in cognitive decline in the Alzheimer’s disease (Saura et al, 2011; Bie et al, 2014) These cell-adhesion molecules are critical for synapse specification and function via interactions with partners that constitute the neurotransmission machinery on both sides of the synapse (Scheiffele et al, 2000; Missler et al, 2003; Graf et al, 2004; Prange et al, 2004; Sara et al, 2005; Gerrow et al, 2006; Chubykin et al, 2007; Mukherjee et al, 2008). Even though NL1 is a postsynaptic protein, altering its expression levels has presynaptic consequences including effects on clustering of synaptic vesicles (Wittenmayer et al, 2009; Dahlhaus et al, 2010) and on the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs; Prange et al, 2004; Nam and Chen, 2005; Chen et al, 2010; Mondin et al, 2011; Burton et al, 2012; Kwon et al, 2012; Schnell et al, 2012)

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Results

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