Alterations of GABAergic Signaling in Autism Spectrum Disorders

Pizzarelli, Rocco; Cherubini, Enrico

doi:10.1155/2011/297153

Cited by 258 publications

(222 citation statements)

References 114 publications

Supporting

Mentioning

207

Contrasting

Unclassified

Order By: Relevance

“…During early development, GABA is an excitatory transmitter. A disturbance in GABAergic function at this stage causes neurodevelopmental disorders, such as mental retardation, Angelman syndrome, epilepsy, and autism (21). Recently, bumetanide has been shown to improve behavior in children with autism by reducing GABAergic excitation (22).…”

Section: Discussionmentioning

confidence: 99%

Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

129

View full text Add to dashboard Cite

The balance between excitation and inhibition is essential for the proper function of neuronal networks in the brain. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) contributes to the network dynamics within the suprachiasmatic nucleus (SCN), which is involved in seasonal encoding. We investigated GABAergic activity and observed mainly inhibitory action in SCN neurons of mice exposed to a short-day photoperiod. Remarkably, the GABAergic activity in a long-day photoperiod shifts from inhibition toward excitation. The mechanistic basis for this appears to be a change in the equilibrium potential of GABA-evoked current. These results emphasize that environmental conditions can have substantial effects on the function of a key neurotransmitter in the central nervous system.S easonal changes in the photoperiod of the Earth's temperate zones affect the behavior and physiology of many organisms (1). The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, can adapt to changes in day length and displays a compressed circadian pattern of electrical activity in short winter days and a decompressed pattern in long summer days (2). This pattern is based on a change in the phase distribution of the activity patterns of individual neurons, which becomes broad in the summer and narrow in the winter (3). The mechanisms that mediate and regulate photoperiod-induced phase distributions are currently not known.The neurotransmitter γ-aminobutyric acid (GABA) is believed to be involved in the phase adjustment and synchronization of the SCN neuronal network (4, 5). GABA and its receptors are expressed in most SCN neurons (6). GABAergic inhibition has been indicated to be important in normal physiological function within the brain. Alterations in this system (i.e., less inhibition) are shown to cause neurological disorders, such as epilepsy and autism (7,8). In addition to its classical inhibitory function within the SCN network, GABA has more recently been shown to also act as an excitatory transmitter, although its exact role is uncertain (4, 9-13). To understand the influence of photoperiod on GABAergic function, we studied synaptic activity, using patch clamp, and GABAergic responses, using Ca 2+ imaging techniques, in the SCN of mice adjusted to long-day and short-day photoperiods. We hypothesized that the narrow, synchronized phase distribution of active neurons during short-day photoperiods would result in increased synaptic activity during the day. Surprisingly, however, exposure to a short-day photoperiod decreased the frequency of spontaneous GABAergic synaptic events compared with the long-day photoperiod.Subsequently, we tested the effect of photoperiod on GABAinduced excitation in the SCN neuronal network. Ca 2+ transients were measured in response to GABA stimulation in long-day and short-day photoperiods. Interestingly, of all cells from the long-day photoperiod, 40% were excitatory and 36% were inhibitory. In contrast, in the short-day photoperiod, 28% of the c...

show abstract

Section: Discussionmentioning

confidence: 99%

Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

129

View full text Add to dashboard Cite

show abstract

“…Epidemiological and genetic studies demonstrated that deficiencies in synapse function 1 are implicated in a wide range of brain disorders, including neurodegenerative 2 and psychiatric diseases such as schizophrenia 3,4 and autism. 5,6 A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. Therefore, the loss or modification of key synaptic proteins might directly affect the properties of such networks and, ultimately, synaptic function.…”

mentioning

confidence: 99%

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

et al. 2015

View full text Add to dashboard Cite

Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels -as occurring in schizophrenia -may contribute to the pathology through an effect on postsynaptic function and plasticity. Cell Death and Differentiation (2015) 22, 1425-1436 doi:10.1038/cdd.2014 published online 13 February 2015 Synapses are complex cellular junctions specialized for communication between neurons. Epidemiological and genetic studies demonstrated that deficiencies in synapse function 1 are implicated in a wide range of brain disorders, including neurodegenerative 2 and psychiatric diseases such as schizophrenia 3,4 and autism. 5,6 A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. Therefore, the loss or modification of key synaptic proteins might directly affect the properties of such networks and, ultimately, synaptic function.SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis 7,8 and which has a role in the regulation of voltage-gated calcium channels. 9,10 The SNAP25 gene has been associated with attention deficit hyperactivity disorder (ADHD) 11,12 and with schizophrenia. 13,14 Consistently, SNAP-25 levels are lower in the hippocampus 15 and in the frontal lobe 16 of patients with schizophrenia. DNA variants of the SNAP25 gene that associate with ADHD are also associated with reduced expression level of the transcript in prefrontal cortex. 17 Finally, reduction of SNAP-25 levels has been found to cause neurodegeneration in mice lacking the synaptic vesicle protein Cysteine-string protein-α, possibly due to the impaired SNARE-complex assembly produced by the decreased SNAP-25. 18 The mechanisms by which reduced SNAP-25 expression may result in a psychiatric disease are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. 19,20 Recently an unexpected postsynaptic role of SNAP-25 has been described, with the protein controlling NMDA and kainate receptor trafficking. 21 Furthermore, it has been lately ...

show abstract

“…GABA also is important in embryonic development, regulating a variety of developmental mechanisms. 8 The other duplicated genes in the region, COX7B2, ATP10D (mitochondrial proteins), COMMD8 (COMM domain containing 8), NFXL1 (zinc-finger protein), NIPAL1, CORIN (pro-ANP to ANP cleavage) CNG1 (cyclic nucleotide gated channel in retinal rod cells), TXK (tyrosine kinase regulating T-cell proliferation), TEC (tyrosine kinase important in osteoclastogenesis), are not involved in a central nervous system development and have not been previously identified as candidate genes in neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

et al. 2013

View full text Add to dashboard Cite

Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABA A ). Clusters of GABA A receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABA A receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABA A receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.

show abstract

Alterations of GABAergic Signaling in Autism Spectrum Disorders

Cited by 258 publications

References 114 publications

Seasonal induction of GABAergic excitation in the central mammalian clock

Seasonal induction of GABAergic excitation in the central mammalian clock

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

Contact Info

Product

Resources

About