Neuroligin-2 Expression in the Prefrontal Cortex is Involved in Attention Deficits Induced by Peripubertal Stress

Abstract

Emerging evidence indicates that attention deficits, which are frequently observed as core symptoms of neuropsychiatric disorders, may be elicited by early life stress. However, the mechanisms mediating these stress effects remain unknown. The prefrontal cortex (PFC) has been implicated in the regulation of attention, including dysfunctions in GABAergic transmission, and it is highly sensitive to stress. Here, we investigated the involvement of neuroligin-2 (NLGN-2), a synaptic cell adhesion molecule involved in the stabilization and maturation of GABAergic synapses, in the PFC in the link between stress and attention deficits. First, we established that exposure of rats to stress during the peripubertal period impairs attention in the five-choice serial reaction time task and results in reductions in the GABA-synthesizing enzyme glutamic acid decarboxylase in different PFC subregions (ie, prelimbic (PL), infralimbic, and medial and ventral orbitofrontal (OFC) cortex) and in NLGN-2 in the PL cortex. In peripubertally stressed animals, NLGN-2 expression in the PL and OFC cortex correlated with attention measurements. Subsequently, we found that adeno-associated virus-induced rescue of NLGN-2 in the PFC reverses the stress-induced attention deficits regarding omitted trials. Therefore, our findings highlight peripuberty as a period that is highly vulnerable to stress, leading to the development of attention deficits and a dysfunction in the PFC GABAergic system and NLGN-2 expression. Furthermore, NLGN-2 is underscored as a promising target to treat stress-induced cognitive alterations, and in particular attentional deficits as manifested by augmented omissions in a continuous performance task.

Prefrontal Nectin3 Reduction Mediates Adolescent Stress-Induced Deficits of Social Memory, Spatial Working Memory, and Dendritic Structure in Mice

“…Accompanying the structural development is the functional maturation of PFC-dependent behaviors, such as social behaviors and working memory [ 6 , 7 ]. Chronic stress during adolescence has been shown to alter prefrontal dendritic architecture and to impair cognitive and social functions [ 8 – 10 ], but the neurobiological mechanisms have just started to be uncovered.…”

“…These molecules are located at adherens and/or synaptic junctions, forming inter-neuronal connections and dynamically shaping synaptic plasticity by modulating synapse formation, maturation, and transmission [ 13 – 15 ]. Several CAMs are altered by stress, such as nectin3 [ 16 , 17 ], nectin1 [ 18 , 19 ], neuroligin2 [ 10 , 20 ], β-catenin [ 21 – 23 ], and N-cadherin [ 22 , 24 ]. Evidence also supports mediating roles of CAMs in the effects of stress on behavior and dendritic structure [ 16 , 20 , 25 , 26 ], but the majority of these studies have focused on the hippocampus and postnatal/adult stress [ 16 , 20 , 25 ].…”

“…Evidence also supports mediating roles of CAMs in the effects of stress on behavior and dendritic structure [ 16 , 20 , 25 , 26 ], but the majority of these studies have focused on the hippocampus and postnatal/adult stress [ 16 , 20 , 25 ]. Only one study has reported the involvement of prefrontal neuroligin2 expression in adolescent stress-induced attention deficits [ 10 ]. Therefore, it remains unknown whether and how prefrontal CAM expression is associated with the behavioral and structural abnormalities induced by adolescent chronic stress.…”

Effect of Increasing Age on Brain Dysfunction in Cirrhosis

“…(33,34) DLG4 receptor knockout animals suffer from defective synaptic plasticity and impaired spatial learning, whereas NLG2 overexpression is associated with attention deficit. (33) Both these cognitive domain alterations are found in patients with cirrhosis, especially those with advancing age. In addition to the increase in NLG2 expression, there was also a higher expression of GABRG1 and GABRB1 mRNA in older cirrhotic mice, which could be potentiated by the NLG2-associated stabilization and maturation of GABA synapses.…”

“…These findings are important because DLG4 expression is critical for the formation of synapses that interact with the excitatory N ‐methyl‐ d ‐aspartic acid, whereas NLG2 is important to stabilize the GABA‐associated inhibitory synapses . DLG4 receptor knockout animals suffer from defective synaptic plasticity and impaired spatial learning, whereas NLG2 overexpression is associated with attention deficit . Both these cognitive domain alterations are found in patients with cirrhosis, especially those with advancing age.…”