The Interplay between Synaptic Activity and Neuroligin Function in the CNS

Table 1

Neuroligin-induced changes in synaptic protein expression.

	Knockout	Acute knockdown	Knock-in	Acute overexpression	Transgenic	Reference
NL1	CA1 HP: vGluT (no), vGAT (no); CA3 HP: vGluT (no), vGAT (no); Layer 2/3 pyramidal neurons: spine density (no); WB of whole brain: synapsin-1a/b (+), NL3 (+), α/β-neurexin (−), PSD-95 (no), vGluT (no), vGAT (no); Cultured cortical neurons: spine density (no); WB of HP: GluA1 (no), GluA2 (−), GluN2A (−), GluN2B (−), GluN1 (−)	DG HP: spine density (−); LA: spine density (no); Layer 2/3 pyramidal neurons: spine density (−); Cultured HP neurons: vGluT (−), vGAT (−), spine number (−)		Cultured HP neurons: spine number (+), GluN1 (+), GluN2A (+), GluN2B (+), PSD95 (+), vGluT (+), vGAT (+), vGluT : vGAT (no), synapsin (+), GluA1 (no) GluA2/3 (+), bassoon (+), synaptophysin (+); Cultured HP neurons (NL1 R473C overexpression): spine number (−), synapsin (−)	NL1 Tg mice: CA1 HP: vGluT (+), vGAT (+), vGluT/PSD-95 cocluster (+), vGAT/gephyrin cocluster (no), spine density (+), spine length (no), spine head (+), spine neck (−), asymmetric synapse (+), symmetric synapse (no), E/I ratio (+); WB: gephyrin (+), PSD-95 (+), vGluT (+), vGAT (+), GluA2/3 (−), NL3 (+), GluA1 (+)	[17, 29, 32, 33, 35, 37, 52–55, 57, 66–68]
NL2	CA1 HP: vGAT (−), vGluT (no), synaptophysin (no), asymmetric synapse (no), symmetric synapse (no), VIAAT (no), gephyrin in pyramidale (−), gephyrin in radiatum (no); CA3 HP: vGAT (−), vGluT (no), synaptophysin (no); GCL: gephyrin (−), VIAAT (no), GABAARγ2 subunit (−); ML: no change in gephyrin, VIAAT, or GABARAγ2; Somatic region of cultured neurons: cytoplasmic gephyrin (+), postsynaptic gephyrin (−); WB of whole brain: synaptobrevin2 (+), no change in several other synaptic proteins; Retina IPL: GABAAα1 (no), GABAAα3 (−), GABAAγ2 (−), gephyrin (no), GlyR (no)	HP cultured neurons: vGluT (−), vGAT (−), spine number (−)		Cultured HP neurons: vGluT (+), vGAT (+), vGluT : vGAT puncta (−), spine density (+), synapsin (no); Dorsal HP (mRNA expression): GAD65 (+), GAD67 (no), vGluT (no), gephyrin (no); Ventral HP (mRNA expression): GAD65 (no),; GAD67 (no), vGluT (no), gephyrin (no)	NL2 Tg mice: mPFC: vGluT (+), vGAT (+), E/I ratio (−); EM of mPFC: total synapse density (+), symmetric synapse (+), asymmetric synapse (no), E/I ratio (−); WB of whole brain: syntaxin (+), vGluT (+), vGAT (+), NL3 (−), NL1 (no), gephyrin (no), PSD-95 (no)	[17, 31, 33, 40, 45, 71–74]
NL3	WB of brain: NL1 (−), vGAT (no), gephyrin (no), vGluT (no); CA1  HP: vGAT (no), vGluT (no), synaptophysin (no); CA3 HP: vGAT (no), vGluT (no), synaptophysin (no); SSC: vGAT (no), vGluT (no)	HP cultured neurons: vGluT (−), vGAT (no), spine number (−)	NL3  R451C KI: CA1 HP: vGAT (+), vGluT (no), synaptophysin (no), spine density (no), stratum radiatum branch points (+); CA3 HP and SSC: vGAT (+), vGluT (no); WB of whole brain: vGAT (+), gephyrin (+), vGluT (no), NL1 (−), NL3 (−); WB of HP: PSD-95 (+), vGluT (no), vGAT (no), NL3 (−), SAP-102 (+), GluA1 (no), NR1 (no), NR2A (+), NR2B (+); EM from layer2/3 of SSC: synapse number (no), asymmetric/symmetric (no), PSD length (no); EM from stratum radiatum CA1 HP: presynaptic nerve terminal size (−), vesicle number (−), spine size (−), PSD length (no), docked vesicle number (no); NL3 R704C KI: WB of whole brain: GluA1 (+), GluA3 (+), NL3 (−), no change in many other synaptic proteins; CA1 HP: synaptophysin (no), vGluT (no), vGAT (no); CA3 HP: synaptophysin (no), vGluT (no), vGAT (no); SSC: synaptophysin (no), vGluT (no), vGAT (no)	Cultured HP neurons: vGluT (+), vGAT (+), vGluT : vGAT (no), synapsin density (+); Cultured HP neurons (NL3 R704C overexpression): synapsin (+), synapse density (+)		[17, 34, 38, 39]
NL4	Retina: GlyRα1 (−), GlyRα2 (no), GlyRα3 (no), GlyRα4 (no)			Cultured HP neurons: spine (+), synapse density (+); Cultured HP neurons (NL4 R87W overexpression): spine (no), synapse density (no)		[13, 21]
NL1/2/3	PBC: vGluT (+), VIAAT (−); IOM: vGluT (+), VIAAT (−); NH: vGluT (no), VIAAT (no); WB: vGluT1 (−), complexin2 (−), αSNAP (−), synaptobrevin (−), synaptophysin (−), synaptotagmin (−), KCC2 (−), GluN1 (−), no change in many other synaptic proteins; Cultured HP neurons: synapsin (no), PSD-95 (no); Cultured cortical neurons: PSD length (no), synaptic cleft width (no), docked vesicle number (no)	Cultured HP neurons: vGluT (−), vGAT (−), spine number (−)				[17, 48]

The synaptic protein-expression changes summarized in the table were all measured in immunohistochemical assays performed on brain slices unless specified otherwise. Other assays: WB, Western blot; EM, electron microscopy. Brain regions: DG, dentate gyrus; LA, lateral amygdala; mPFC, medial prefrontal cortex; HP, hippocampus; GCL, granule cell layer; SSC, somatosensory cortex; PBC, pre-Botzinger complex; ML, molecular layer; NH, hypoglossal nucleus. Detected changes: +, increase; −, decrease; no, no significant change.