Potential for treatment of severe autism in tuberous sclerosis complex

Table 3 Selected preclinical models of tuberous sclerosis complex

Model	Genetic manipulation	Behavioral effects	Seizures	Autism	Synaptic plasticity	Neuropathology	Rapamycin	Ref.
Tsc1+/- mice	Heterozygous Tsc1 deletion, exons 6-8	↓Hippocampal dependent learning	None	↓Social interaction	-	None	-	[58]
Tsc2+/- Eker rat	Spontaneous autosomal dominant (Heterozygous)	-	-	-	↓LTP, ↓LTD, ↑PPF	-	-	[61]
Tsc2+/- Eker rat	Spontaneous autosomal dominant (Heterozygous)	No learning and memory deficits	No spontaneous	↓Social interaction, ↓↓ after seizure induction	-	-	-	[59]
Tsc2+/-	Heterozygous disruption in second exon	↓Hippocampal dependent learning	-	-	↓Threshold for L-LTP	-	Reversed all	[93]
Tsc2+/- or WT pups from Tsc2+/- or WT dams	Heterozygous Tsc2 deletion	↑Maternal care by Tsc2+/- dams	-	↑Vocalization in WT and Tsc2+/- pups of Tsc2+/- dams	-	-	-	[60]
Tsc2+/-	Heterozygous Tsc2 deletion	-	-	-	↓mGluR-LTD,	-	Reverses deficits in protein-synthesis-dependent mGluR-LTD	[62]
					↓Arc synthesis
Tsc1fl/flNestin-rtTA(+)TetOp-cre(+)	Mosaic homozygous Tsc1 deletion in cortical neural progenitors	-	Yes+	-	-	Heterotopias with enlarged, pS6+ neurons	↑Survival, ↓seizures, ↓neuropath	[94]
						White matter nodules
Tsc1fl/-Syn1-Cre	Homozygous Tsc1 deletion in neurons from mid-gestation; (heterozygous in all other cells)	-	Yes+	-	-	Dysplastic neurons	↑Survival, ↑myelination, ↑body weight, ↓neurologic impairment	[95,96]
						↓Cortical organization
						↓Myelin
Tsc1fl/fl Emx1-Cre	Homozygous Tsc1 deletion in early embryonic neural progenitors	-	Yes+	-	-	↓Cortical organization	↓Seizures, ↑survival, ↓glial abnl, ↑weight, ↓brain size	[97]
						↑Brain size
						↓Myelin
						tHick astrocyte processes
Tsc1fl/fl Nestin-Cre	Homozygous Tsc1 deletion in differentiating neurons	-	-	-	↑EPSCs	↑Cell size	↓Spine width ↑spine length	[98]
					↑AMPA	↑Spine width
						↑Spine length
						↓Spine density
Tsc1fl/fl Syn1-Cre	Homozygous Tsc1 deletion in neurons	-	No spontaneous	-	↑EPSCs	No gross abnormalities	-	[99]
			Epileptiform discharges		↑AMPA
Tsc1fl/fl GFAP-Cre	Homozygous Tsc1 inactivation in glial-fibrillary acidic protein (GFAP)-+ cells		Yes+, ↓Glt1			↑Astrocytes	↑Glt1, ↑survival ↓neuropath Early: prevented epilepsy, Late: decreased seizure frequency	[100,101]
						↑Brain size
						↓Hippocampal organization
Tsc2fl/fl GFAP-Cre	Homozygous Tsc2 inactivation in GFAP + cells	-	Yes++, ↓Glt1	-	-	↑Astrocytes	↑Survival, ↓seizures, ↓neuropath	[102]
						↑Brain size
						↓Hippocampal organization
Tsc1fl/+L7-Cre, or Tsc1fl/flL7-Cre	Heterozygous or homozygous Tsc1 deletion limited to cerebellar Purkinje cells	Normal acquisition, ↓reversal of spatial learning in homozygous mutants	-	↓social interaction in both genotypes ↑grooming, vocalization	PC ↓excitability in heterozygous, ↓↓ in homozygous	PC loss in homozygous, ↑PC dendritic spine density in both heterozygous and homozygous	Reversed pathological and behavioral abnormalities	[64]
Tsc2fl/- , or Tsc2fl/-Pcp2-Cre	Heterozygous Tsc2 deletion (global), or homozygous Tsc2 deletion in cerebellar Purkinje cells, heterozygous in other cells	-	-	↑repetitive behavior in homozygous, ↓social interaction in both genotypes	-	PC loss in homozygous,	Reversed social deficits	[63]

These are existing preclinical models designed to re-capitulate neurologic features of tuberous sclerosis complex (TSC). - Not examined; +: Mild seizure severity; ++: Moderate seizure severity.