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Review
. 2018 Feb;48:122-130.
doi: 10.1016/j.conb.2017.12.003. Epub 2017 Dec 23.

NLGN1 and NLGN2 in the Prefrontal Cortex: Their Role in Memory Consolidation and Strengthening

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Free PMC article
Review

NLGN1 and NLGN2 in the Prefrontal Cortex: Their Role in Memory Consolidation and Strengthening

Aaron Katzman et al. Curr Opin Neurobiol. .
Free PMC article

Abstract

The prefrontal cortex (PFC) is critical for memory formation, but the underlying molecular mechanisms are poorly understood. Clinical and animal model studies have shown that changes in PFC excitation and inhibition are important for cognitive functions as well as related disorders. Here, we discuss recent findings revealing the roles of the excitatory and inhibitory synaptic proteins neuroligin 1 (NLGN1) and NLGN2 in the PFC in memory formation and modulation of memory strength. We propose that shifts in NLGN1 and NLGN2 expression in specific excitatory and inhibitory neuronal subpopulations in response to experience regulate the dynamic processes of memory consolidation and strengthening. Because excitatory/inhibitory imbalances accompany neuropsychiatric disorders in which strength and flexibility of representations play important roles, understanding these mechanisms may suggest novel therapies.

Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
Representation of excitatory and inhibitory neuron types in the prefrontal cortex (highlighted in blue, left). Excitatory pyramidal neurons (Pyr) receive perisomatic inhibition from parvalbumin-positive interneurons (PV+) and dendritic inhibition from somatostatin-positive interneurons (SST+). SST+ neurons also provide dendritic inhibition onto PV+ neurons. Vasoactive intestinal peptide–positive neurons (VIP+), a subpopulation of 5-hydroxytryptamine-3a receptor (5HT3aR)-expressing interneurons, inhibit PV+ and SST+ inhibitory neurons, resulting in disinhibition of Pyr neurons.
Figure 2
Figure 2
Neuroligin 1 (NLGN1) and NLGN2 cell adhesion molecules at excitatory and inhibitory synapses, respectively. NLGN1 and NLGN2 are enriched are postsynaptic membranes, and their extracellular domains adhere to distinct isoforms of neurexins (NRXN) at presynaptic membranes. Intracellularly, NLGN1 binds to the scaffolding protein postsynaptic density protein 95 (PSD95), and regulates the synaptic localization of glutamate receptors (GluR) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs). NLGN2 forms a complex with collybistin (CB) and gephyrin (GPHN) and regulate the synaptic localization of GABA receptors (GABAR). The cell-surface molecules MAM domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) form post-synaptic cis-complexes with NLGN1 and NLGN2, and negatively regulate their trans-synaptic adhesion with NRXNs [60-62]. Additional protein abbreviations: GlyR, glycine receptor; P, PDZ binding domain; S, Src homology domain (SH3 domain); GK, guanylate kinase domain; D, Dbl homology domain; P, Pleckstrin homology domain (Adapted from Bemben et al., 2015 [48]).
Figure 3
Figure 3
Neuroligin 1 (NLGN1) and NLGN2 play distinct roles in memory consolidation, strengthening, and extinction inhibition. (A) Schema of behavioral procedures, representative images and relative quantitative western blot analyses of PL cortex. Protein extracts were obtained from rats trained (Tr) in inhibitory avoidance (IA) and given 3 brief memory retrievals (3Rs), which consisted of 10 sec exposures to the training context without footshock, every two days. Rats were euthanized (red arrows) one hour after 3Rs or at the matched time point for the group that underwent training without retrievals and remained in the home cage after training (NoR). Naïve rats (N) served as reference controls. Data are presented as mean percentage ± s.e.m. of the mean values of the N group. One-way ANOVA followed by Newman-Keuls post hoc test; NLGN1 n = 9–10, NLGN2 n = 9–10; *p < 0.05 for both comparisons. (B) Schema of behavioral procedures is given above the graphs. Rats were trained (Tr) in IA and given 3Rs every two days or left in the home cage without retrieval (NoR) after training. Thirty minutes before each reactivation, or at matched timepoints in the NoR group, the animals received a bilateral PL cortex injection (black arrows) of NLGN2 recombinant extracellular domain (NLGN2inh) to inhibit NLGN2 function. Animals were tested for memory retention two days after the last retrieval (T1), and again five days later (T2), as shown in the schema. A reminder footshock (RS) was given in a different context with the same shock intensity one day after T2 and memory was tested one day later (T3). Data are expressed as mean latency ± s.e.m. Two-way ANOVA followed by Bonferroni post hoc test; *p<0.05, ***p<0.001 n = 7-10 (Adapted from Ye et al., 2017 [11]).
Figure 4
Figure 4
Schematic representation of our working model for cell type–specific changes in NLGN1 and NLGN2 after IA training and retrieval-induced memory strengthening in the PL cortex. IA training may increase NLGN2 expression in parvalbumin-positive interneurons (PV+), which would lead to disinhibition of pyramidal (Pyr) cells, as well as NLGN1 in Pyr cells. These changes would result in increased E/I. Memory retrieval-induced strengthening would decrease NLGN2 levels in Pyr cells, while maintaining NLGN2 increased levels in PV+ neurons. These changes would further increase excitation. Together, these NLGN1 and NLGN2 changes on different neuronal populations would differentially regulate E/I balance in memory consolidation and following retrievals leading to memory strengthening.

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