Increased Dentate Gyrus Excitability in Neuroligin-2-Deficient Mice in Vivo

Abstract

The postsynaptic adhesion protein neuroligin-2 (NL2) is selectively localized at inhibitory synapses. Here, we studied network activity in the dentate gyrus of NL2-deficient mice following perforant path (PP) stimulation in vivo. We found a strong increase in granule cell (GC) excitability. Furthermore, paired-pulse inhibition (PPI) of the population spike, a measure for γ-aminobutyric acid (GABA)ergic network inhibition, was severely impaired and associated with reduced GABA(A) receptor (GABA(A)R)-mediated miniature inhibitory postsynaptic currents recorded from NL2-deficient GCs. In agreement with these functional data, the number of gephyrin and GABA(A)R clusters was significantly reduced in the absence of NL2, indicating a loss of synaptic GABA(A)Rs from the somata of GCs. Computer simulations of the dentate network showed that impairment of perisomatic inhibition is able to explain the electrophysiological changes observed in the dentate circuitry of NL2 knockout animals. Collectively, our data demonstrate for the first time that deletion of NL2 increases excitability of cortical neurons in the hippocampus of intact animals, most likely through impaired GABA(A)R clustering.

Molecular and functional heterogeneity of GABAergic synapses

“…Although preservation of gephyrin clusters might point to a functional homologue of CB, the phenotype of Purkinje cells rather indicates that clustering of gephyrin and of GABA A R depends on different mechanisms, with only the former requiring the presence of CB. In NL2-KO mice, differential loss of postsynaptic clusters was observed in different subcellular compartments of CA1 pyramidal cells and dentate gyrus granule cells, with the main disruption of gephyrin and GABA A R clusters occurring on the soma, at synapses formed by basket cells [78,79,35]. Thus, these reports pointed to distinct clustering mechanisms for postsynaptic proteins of perisomatic versus dendritic GABAergic synapses.…”

“…Further, this association raises the unresolved issue whether the DGC requires NL2 for localizing at GABAergic synapses. 7) Disruption of gephyrin and GABA A R clusters in perisomatic, but not dendritic synapses of hippocampal neurons of NL2-KO mice [79,35] suggests that NL2 is the only NL isoform that interacts with S-SCAM/β-dystroglycan [102] and indicates that postsynaptic clustering of GABA A R requires the presence of a NL isoform. As a corollary, gephyrin cluster preservation in dendritic synapses of NL2 mice suggests compensation by another NL isoform.…”

Drosophila Neuroligin3 Regulates Neuromuscular Junction Development and Synaptic Differentiation

“…5D), and we found that the distribution and level of these proteins appeared normal in dnlg3 mutants. Previous studies have indicated that Nlgs are important for synaptic targeting of postsynaptic receptors (32,33). We also examined postsynaptic receptors; at NMJs, there are two subtypes of glutamate receptors characterized by the presence of either the GluRIIA or GluRIIB subunit together with shared GluRIII, GluRIID, and GluRIIE.…”

Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo

“…Electrophysiological characterization of APP knockout and wildtype mice was carried out as described before (Jedlicka et al 2009a;Winkels et al 2009;Jedlicka et al 2011). Briefly, mice were anesthetized with an intraperitoneal injection of urethane (Sigma Aldrich, St. Louis, MO, USA; 1.2 g/kg body weight, supplemental doses of 0.3-1 g/kg s.c. g/kg as needed).…”