JPCB Journal

1.      Editorial

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by repetitive behaviors and deficit in social interaction and communication [1]. CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network estimated about 1 in 68 children has been identified withAutism Spectrum Disorder (ASD). This ismore common in boys than girls.

 2.      Neural Plasticity in ASD

 Synaptic dysfunction is hallmark of ASD [2] leads to overgrowth and hyperexcitability in early development [1]. In addition, change in excitatory drive and activity pattern along with cascading change in network function via plasticity mechanisms have been reported in ASD patients.

 During normal development human cortex undergo dynamic change of synaptic connections by synaptic pruning leads toLong Term Depression (LTD) [2]. However, these are impaired in ASD. The increase in dendritic spines in the cortex of individuals with autism, support this hypothesis [3,4]. 

Importantly, several studies have reported dysregulation of LTD across different genetic abnormalities and across different brain areas which is reported in several animal models. Santini et al 2013[5]demonstrated transgenic mice that overexpress the eukaryotic translation initiation factor 4E (eIF4E), which is regulated by FMRP, similarly show ASD-like behavioral alterations, enhanced spinedensity, enhanced mGluR-LTD in the hippocampus and, in addition, enhanced tetanization-evoked LTD in the striatum. Auerbach et al 2011[6]reported reduced hippocampal LTD in Tsc2^+/− mice.  Huber et al 2002 and Verheij et al 1993[7,8] have reported enhanced mGluR5- dependent in the hippocampus of Fmr1knockout mice.

 3.      Excitatory/Inhibitory Imbalance 

Chattopadhyaya, Cristo 2012 andHutsler, Zhang 2010[9,10]have discovered structural/functional changes in both glutamatergic excitatory and GABAergic inhibitory circuits in postmortem studies in individuals with ASD. Toro et al, 2010[11]proposed most emerging hypothesis of alterations in the ratio of excitatory to inhibitory cortical activity (E/I imbalance). Such imbalances may arise from problems in initial neural circuit formation or maintenance.A study by Rubenstein and Merzenich, 2003 [12]proposed increase in ratio of excitation to inhibition in ASD.

There are several factors influencing to synaptic E/I balance would include excitatory/inhibitory synapsedevelopment, synaptic transmission and plasticity, downstream signaling pathways, homeostatic synaptic plasticity, and intrinsic neuronal excitability[13].

 3.1.  Lowering Inhibitory Drive

 Several studies in humans and animals reported alterations in GABAergic circuits in ASD.A Fatemi et al 2002 andYip et al 2007[14,15]have found significant reduction in GAD65/GAD67 levels in the parietal cortex and cerebellum. However, Fatemiet al 2002, Collins et al 2006 and Oblak et al 2010[14,16,17] have reported alterations in GABA_A and GABA_B receptors in postmortem brains of autistic subjects. Additionally, Zikopoulos and Barbas 2013 [18] has reported lower numbers of PV+ interneurons in the prefrontal cortex, a reduction in its absolute number could explain the aberrant GABAergic transmission in autism [19]. Bateup et al 2013[20]showed loss of TSC1, a gene encoding a regulator of mTOR signaling in hippocampal cultures resulted in a primary decrease of inhibitory synaptic transmission.

 Together, these results suggest heterogenous changes in glutamatergic and GABAergic systems in the ASD brain can converge upon an overall increased ratio of excitation/inhibition, which can manifest in epileptic symptoms, macroscopic changes in brain volume, and behavioral alterations.

 3.2.  Increase in Excitatory Drive

 A study by Gupta et al (2015) [21] had demonstrated that Glutamate delta1 receptor (GluD1) plays an important role in Autism Spectrum Disorder (ASD) like features in mice model. Disrupting GluD1 resulted into autism like phenotype and molecular abnormalities similar to ASD. GluD1 knockout mice show increase in dendritic spine density, frequency of miniature excitatory post synaptic currents (mEPSCs) co-localization of PSD95 and synaptophysin (a marker of excitatory synapses) in medial prefrontal cortex and CA1 region of hippocampus suggest more excitatory drive in these brain regions and modulate E/I balance.

 One possible biological mechanism connecting the two phenotypes is increased spine density, as recent evidence examining post-mortem ASD human brain tissue revealed an increase in spine density on apical dendrites of pyramidal neurons from cortical layer 2 in frontal, temporal and parietal lobes and layer 5 in the temporal lobe [10]. Furthermore, these trends are also observed in tissue from individuals with diseases co-morbid with autism. For instance, the fragile X brain is characterized by macrocephaly, elevated spine density and elongated, tortuous spine morphologies [22].

 The imbalance reported in excitatory and inhibitory circuit was normalized bypharmacological, genetic and optogenetic manipulation of specific excitatory and inhibitory component directly caused changes in social and cognitive behavior in mice [23]. Therefore, circuitlikely to be plastic during postnatal development; notably, several neurodevelopmental disorders, including ASD manifest during this plasticity period[24,25].

 Physiological mechanisms of E/I imbalance in ASDs are more intricate. Several studies have shown that the same gene mutation leads to distinct synaptic E/I imbalances in different synapses, cell types, and brain regions at different time points. Therefore, studies from various groups highlighted the importance of pursuing detailed and integrative analyses of E/I imbalances in future studies of animal models of ASD.

1.      de Lacy N, King BH (2013) Revisiting the relationship between autism and schizophrenia: toward an  v    integrated neurobiology. Annu Rev ClinPsychol 9: 555-587. 
2.   Piochon C, Kano M, Hansel C (2016)LTD-like molecular pathways in developmental synaptic pruning.Nat Neurosci 19: 1299-1310.
3.       Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14: 285-293.
4.       Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, et al. (2014) Loss of mTOR-dependent macro autophagy causes autistic-like synaptic pruning deficits. Neuron 83: 1131-1143.
5.       Santini E, TN Huynh, AF MacAskill, AG Carter, P Pierre, et al. (2013) Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493: 411-415.
6.       Auerbach BD, Osterweil EK & Bear MF (2011) Mutations causing syndromic autism to define an axis of synaptic pathophysiology. Nature 480: 63-68.
7.       Huber KM, Gallagher SM, Warren ST & Bear MF (2002) Altered synaptic plasticity in a mouse model of                 fragile X mental retardation. Proc Natl Acad Sci USA 99: 7746-7750.
8.       Verheij C, Bakker CE, de Graaff E, Keulemans J, Willemsen R, et al. (1993) Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 363: 722-724.
9.       Chattopadhyaya B, Cristo GD (2012) GABAergic circuit dysfunctions in neurodevelopmental disorders. Front Psychiatry 3: 51.
10.    Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309: 83-94. 
11.    Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, et al. (2010) Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet 26: 363-372.
12.    Rubenstein JL, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes brain and behavior 2: 255-267.
13.    Lee E, Lee J, Kim E (2016) Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders.Biol Psychiatry S0006-3223: 32387-32393.
14.    Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, et al. (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological psychiatry 52: 805-810.
15.    Yip J, Soghomonian JJ, Blatt GJ (2007) Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol 113: 559-568.
16.    Collins AL, Ma D, Whitehead PL, ER Martin, HH Wright, et al. (2006) Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics 7: 167-174.
17.    Oblak AL, Gibbs TT, Blatt GJ (2010) Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem 114: 1414-1423.
18.    Zikopoulos B, Barbas H (2013) Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci 7: 609.
19.    DeFelipe J (1999) Chandelier cells and epilepsy. Brain 122: 1807-1822.
20.    Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, et al. (2013) Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78: 510-522.
21.    Gupta SC, Yadav R, Pavuluri R, Morley BJ, Stairs DJ, et al. (2015) Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity. Neuropharmacology 93: 274-284.
22.    Irwin SA, Patel B, Idupulapati M, Crisostomo RA, Larsen BP, et al. (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 98: 161-167.
23.    Yizhar O, Fenno LE, Prigge M, F Schneider,   TJ Davidson, et al. (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477: 171-178.
24.    Zoghbi HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302: 826-830.
25.    Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD (2009) GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord 39: 223-230.