vissa former av autism

ASD comprises a heterogeneous group of disorders with different etiologies, phenotypic outcomes and ages of onset. In a subset of patients with ASD, mutations of genes related to synaptic function have been identified, suggesting that abnormal neuronal homeostasis is a risk factor for ASD1, 2. Studies of the human brain transcriptome have shown that genes associated with synaptic functions may be expressed early during intrauterine development (3–6 months gestational age)3. However, the consequences of these alterations in gene expression are only detected as ASD much later, during the first 3 years of life. It is not known whether neuronal circuits expressing these genes can be preserved despite the presence of genetic mutations. An increasing number of studies in mouse models of ASD have shown that certain neuronal defects can be reversed in the mature mouse brain, either by restoring the gene function, decreasing mRNA translation or modulating the balance between excitation and inhibition (Table 1 and Supplementary Table 1). These results challenge the notion that all forms of ASD are irreversible neurodevelopmental disorders4. Given the clinical heterogeneity of ASD, we argue that specific synaptic clinical trials should be designed and launched with a view to establishing whether or not similar reversals could also occur in humans.

Table 1: Improvement of the phenotypes in mouse models of autism spectrum disorders

From Progress toward treatments for synaptic defects in autism
Richard Delorme,
Elodie Ey,
Roberto Toro,
Marion Leboyer,
Christopher Gillberg
& Thomas Bourgeron
Nature Medicine 19,685–694(2013)doi:10.1038/nm.3193
back to article

Table 1: Improvement of the phenotypes in mouse models of autism spectrum disorders

Models

Methods

Outcomes

*Treatment administered during development. PPI, prepulse inhibition; LTD, long-term depression; LTP, long-term potentiation; PAG, periaqueducal gray; USV, ultrasonic vocalizations; DHPG, dihydroxyphenylglycine.


Fmr1−/−

Genetic

Overexpression of FMR1 human gene37*38*113*

No effect: Motor learning; spatial learning and memory; anxiety; startle response (worse)
Improvement: Macroorchidism; activity; social approaches; anxiety toward novel food; PPI



Reduction of mGluR5 expression42*

No effect: Macroorchidism
Improvement: Extinction of inhibitory avoidance; plasticity and spine density in visual cortex; basal protein synthesis in hippocampus; audiogenic seizure; body growth



Overexpression of Nlgn141*

No effect: Spatial learning; interest for novel objects
Partial improvement: Positive puncta for excitatory synapses; number of inhibitory synapses
Improvement: Social preference; social contact maintenance; activity; body weight




Pharmacology

MPEP (mGluR5 antagonist)43, 114

Partial improvement: Seizure
Improvement: Anxiety in open field; activity; seizure



Minocycline (matrix metalloproteinase 9 inhibitor)48*49*

Improvement: Working memory in Y-maze; anxiety in plus maze; percentage of mushroom-shaped spines; dendritic spine length; percentage of short dendritic spines with larger heads; number of USV emitted by a male toward a female


CTEP (mGluR5 antagonist)68

No effect: Motor coordination
Partial improvement: ERK activity; macroorchidism
Improvement: Inhibitory avoidance; startle response to auditory stimuli; activity; spine density in visual cortex; hippocampal LTD (slices)


Arbaclofen (activation of GABAB receptor)78

No effect: Distance in open field; marble burying; motor coordination
Partial improvement: Seizure
Improvement: Basal protein synthesis in hippocampus; AMPA receptor internalization; spine density


Lovastatin (ERK-mediated protein synthesis inhibitor)72

Partial improvement: Audiogenic seizures
Improvement: Excessive protein synthesis, epileptiform activity in hippocampus (in vitro), hyperexcitability in visual cortex (in vitro)



Environment

Physical enrichment33

Improvement: Anxiety in open field; habituation to novel objects; basal dendritic branching; basal dendritic length; spine density; spine maturation; GluR1 levels in visual cortex



Nlgn3–/–

Genetic

Reexpression of Nlgn3 in Purkinje cells71*

Partial improvement: Motor coordination
Improvement: mGluR1α protein level; mGluR1α synaptic abundance; DHPG-induced phospho-GluA2 signals; ectopic synapse formation



Nlgn1−/−

Pharmacology

D-Cycloserine (NMDAR partial agonist)52

Improvement: Self-grooming



Pten−/−

Pharmacology

Rapamycin (mTOR inhibitor)64

No effect: Cell polarity
Partial improvement: Macrocephaly
Improvement: Social interactions; anxiety; soma hypertrophy



Shank2−/−

Pharmacology

D-Cycloserine (NMDAR partial agonist)51

No effect: Social recognition
Partial improvement: Preference for social interactions
Improvement: NDMA/AMPA ratio



CDPPB (mGlur5 positive allosteric modulators)51

No effect: Social recognition; pup retrieval; repeated jumping; anxiety in plus maze; activity
Partial improvement: Preference for social interactions
Improvement: NMDA/AMPA ratio; LTP and LTD at hippocampal Schaffer-collateral–CA1-pyramidal synapses; NMDAR signaling in whole brain and synaptosomes



Cntnap2−/−

Pharmacology

Risperidone (dopaminergic D2 receptor antagonist)54

No effect: Sensory hypersensitivity; preference for social interactions
Partial improvement: Spontaneous alternations
Improvement: Nesting behavior; self-grooming; hyperactivity



Scn1a+/−

Pharmacology

Clonazepam (positive allosteric modulator of GABAA)77

Improvement: Social interest; free social interactions; fear conditioning; inhibitory transmission



Eif4ebp2−/−

Pharmacology

4EGI-1 (selective inhibitor which prevents eIF4E binding to eIF4G)110

Improvement: Social preference; Nlgn protein amounts; excitation–inhibition balance



Tsc1−/−

Pharmacology

Rapamycin (mTOR inhibitor)61

Partial improvement: Survival; macrocephaly; hindlimb clasping



Tsc2−/−

Pharmacology

Rapamycin (mTOR inhibitor)61

Improvement: Spatial learning; context discrimination; L-LTP



Mecp2y/–

Genetic

Reactivation of Mecp2 (Cre-lox)4, 115

Partial improvement: Activity; gait; hindlimb clasping; tremor; respiratory function; body weight
Improvement: LTP; activity; body weight; brain weight; neuronal size



Overexpression of BDNF45*

Partial improvement: Brain size
Improvement: Activity



Pharmacology

Ampakine CX546 (AMPAR agonist)116

Partial improvement: BDNF levels
Improvement: Respiratory function


Desipramine (norepinephrine reuptake inhibitor)117, 118

No effect: Activity; body weight; head size
Partial improvement: Respiratory function; lifespan
Improvement: Tyrosine hydrolase expression in brainstem



Insulin-like growth factor 1 (IGF1R agonist)34*

Partial improvement: Lifespan; activity; respiratory function; heart rate; brain weight; PSD-95 concentration in motor cortex; spine density on motor cortex neurons; excitatory synaptic transmission in sensory motor cortex neurons; plasticity in cortical circuits



Insulin87

No effect: baseline breathing; breathing response to hypoxia
Worsening: weight gain; heart rate decline; blood glucose; breathing response to hypoxia; lifespan


Fingolimod (sphingosine-1 phosphatase receptor modulator)53

No effect: BDNF levels in cerebellum
Partial improvement: Lifespan; hindlimb clasping; BDNF levels in cortex, hippocampus, striatum; wet weight of striatum
Improvement: Locomotor activity; motor coordination



Environment

Physical enrichment81

No effect: Motor coordination; BDNF levels in cerebellum



Del15q11–13

Genetic

Reduction of CaMKII inhibitory phosphorylation117*

Improvement: Motor coordination; spatial learning and memory; contextual fear conditioning; kinase activity; body weight; audiogenic seizure; LTP



Ube3amat–/pat+

Pharmacology

PD158780 and PD168393 (ERBBB inhibitor)118

Improvement: LTP, long-term memory in fear conditioning



Dup17q11.2

Environment

Physical and social enrichment83

No effect: Social dominance; olfactory habituation/dishabituation; stereotypes
Partial improvement: Social recognition; fear conditioning; anxiety
Improvement: Motor coordination


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Schematic representation of pre- and post-synaptic proteins located at glutamatergic and GABAergic synapses. Proteins reported to be associated with ASD are in orange. Factors involved in the pathways that the ASD-associated proteins participate in are shown in blue. Pharmacological compounds used to reverse core symptoms of autism in mouse models and patients are tagged with a star. The functional link between these proteins were shown experimentally (for example: FMRP targets distinct mRNA sequence elements to regulate expression of several proteins associated with ASD109 and eIF4E overexpression leads to increased translation of neuroligins110, which are postsynaptic proteins that are causally linked to ASDs111). The pathways associated with ASD are reviewed in refs. 2, 56, 112.