The animals behaved normally in a wide range of behavioral tests except when exposed to aversive situations caused by either natural or CI994 datasheet conditioned fear stimuli. Under such conditions, enhanced anxiety responses and a bias for threat cues were observed.22 The bias of the animals for threat

cues was especially significant since this behavior Inhibitors,research,lifescience,medical corresponds to the cognitive deficit contributing to the inability of anxious individuals to distinguish an ambiguous from a threatening situation.23 Thus, a GABAA receptor deficit is considered as a predisposition for anxiety disorders in humans. It appears that anxiety symptoms are a sensitive manifestation of an impaired GABAergic neurotransmission.21,22,24 Epilepsy Modification of activity at GABAergic synapses powerfully influences Inhibitors,research,lifescience,medical epileptic phenomena. This is a consequence of the role of GABAergic synapses in recurrent inhibitory systems in cortical and other structures, and their effect in limiting the excessive discharge of principal neurons in time and space. Genetic evidence provided the most direct link of epilepsy to GABAA receptor dysfunction. A K289M mutation located in the extracellular loop Inhibitors,research,lifescience,medical of the γ2-subunit

between the transmembrane domain 2 and 3, was linked to familial generalized epilepsy with febrile seizures.25 At recombinant GABAA receptors, the K289M mutation reduced the GABA-activated current. Another mutation in the γ2-subunit Inhibitors,research,lifescience,medical of GABAA receptor was linked to childhood absence epilepsy and febrile seizures with a conserved arginine residue being mutated to glutamine (R43Q).26 However, since childhood absence epilepsy is not inherited in a simple mendelian manner,

the point mutation is not Inhibitors,research,lifescience,medical considered to be sufficient by itself to cause this phenotype. Another example of an altered GABAergic function is that of generalized seizures in infancy related to a pyridoxine deficiency. Since pyridoxal phosphate is a cofactor of glutamic acid decarboxylase, the seizures are related to a deficient synthesis of GABA and can be treated by moderate or high doses of pyridoxine. Furthermore, multiple others forms of epilepsy occur in the neurodevelopmental disorder, known as Angelman syndrome, which also shows mental retardation and facial dysmorphism. Genetic studies commonly reveal a major deletion on maternal chromosome 15q11-1327 with two genes being the major contributors to the syndrome – one is UBE3A, encoding a ubiquitin ligase, the other is GABRB3 encoding the β2 subunit of GABAA receptor. Absence epilepsy in man, with a 2- to 3-Hz spike-and wave discharge in the cortex, is dependent on a thalamocortical loop, which involves several sets of GABAergic synapses in cortex and thalamus. The “waves” correspond to hyperpolarizing activity resulting from synchronous firing of GABAergic neurons.28 The effects of GABA-related drugs are however complex.