Table 1.

Summary of Synj1 models and phenotypes.

	In vivo models	In vivo phenotypes	citations	In vitro sample origin	In vitro phenotypes	citations
Deficient models	KO mouse	Perinatal lethal and diminished embryonic growth rate	[3]	Rodent brain	Accumulation of brain PI(4, 5)P2 and PI(3,4,5)P3 Accumulation of Clathrin coated vesicles Slow endocytosis kinetics Impaired AMPA receptor trafficking Impaired astrogliogenesis Hyperactive autophagosome formation in astrocyte	[3,15,28,29]
	HET mouse	Age-dependent hyperactive locomotion followed by motor deficit Reduced DA metabolism Loss of striatal DAergic terminals in aged mice	[16,21]	Rodent brain	Midbrain neuron-specific impairment in synaptic endocytosis Normal endocytosis in cortical and hippocampal neurons Normal exocytosis	[15,16,21]
	KO Drosophila eye	Capable of detecting light and display phototaxis	[5]	Drosophila photoreceptor	Densely clustered and Clathrin coated vesicles Impaired endocytosis at high frequency stimulation Normal exocytosis	[5]
	KO Zebrafish	No optokinetic response Abnormal retina cone receptors, but normal rods 3. Abnormal swim behavior	[38,60]	Zebrafish photoreceptor	Enlarged Acidic vesicles Irregular late endosome impaired autophagy clearance Abnormal localization of synaptobrevin and RibeyeB	[38]
	KO C. elegans	Diminished locomotion rates Abnormalities associated with loss of GABA and cholinergic transmission	[6]	C. elegans NMJ	Accumulation of clathrin coated vesicles and clahtrin coated pits Depletion of synaptic vesicles Increased endosomes	[6]
				Heterologous cells expressing Synj1 shRNA	Increased number and size of early endosomes Normal late endosomes Intracellular accumulation of transferrin receptors	[33]
Overexpression models	Human with DS			Human blood cells	Increased size of early endosomes	[41]
	Human with DS/AD			Postmortem human brain	Reduced Synaptophysin level	[61]
	Synj1 BAC transgenic Mouse	Learning deficits in the Morris water maze task Hippocampal dependent memory and cognitive deficits	[40,41,61]	Mouse brain	Decreased brain PI(4,5)P2, increased brain PIP Increased size of early endosomes in the prefrontal cortex neurons Hippocampal hyperexcitability Place cell dysfunction	[41,61].
Knock-in models				SYNJ1 R258Q patient-derived human induced neurons	Accumulation of WIPI2/Atg18a in neurites	[37]
	R258Q KI Mouse	Shortened lifespan Motor function deficits	[14]	Mouse brain	Accumulation of clathrin coated vesicles at synapse Accumulation Parkin, Amphiphysin 2, Auxilin, and Clathrin light chain Dystrophic DAergic axon and clustering of DAT in the dorsal striatum Normal early endosome and lysosome	[14,51]
	R258Q KI Drosophila	Viable but reduced lifespan upon starvation Normal retina function	[37]	Drosophila NMJ	Impaired autophagosome formation in response to synaptic activity and starvation	[37]
	Synjl C378S, D380N KI C. elegans	Normal EPSC from muscle wall recording	[20]	Synj1 C383S KI mouse cortical neuron	Impaired endocytosis after small stimuli Normal endocytosis during persistent synaptic activity	[15]
	Synj1 ΔSAC1 KI C. elegans	Impaired EPSC from muscle wall recording Impaired Synj1 synaptic localization	[20]	Synj1 R258Q KI mouse cortical neuron	Impaired endocytosis after small stimuli Normal endocytosis during persistent synaptic activity	[14]
	Synj1 D716A KI C. elegans	Impaired locomotion Reduced EPSC from muscle wall recording	[20]	Synj1 D730A mutant KI mouse cortical neuron	Impaired endocytosis during persistent synaptic activity Impaired endocytosis following short stimuli Impaired SV re-availability	[15]
	Synjl ΔPRD KI C. elegans	Normal locomotion Normal EPSC from muscle wall recording Ipaired Synj1 synaptic localization	[20]	Synjl endophilin binding mutant (EBM) KI mouse cortical neuron	Impaired endocytosis during persistent synaptic activity Partially impaired SV re-availability Normal Synj1 synaptic localization	[15]