Polymorphisms of the subunits of the NMDA receptor (N-methyl-D-aspartate) have been identified in people with schizophrenia, autism spectrum disorders, and intellectual disabilities.
Neurophysiological studies of these clinical conditions have revealed neuronal synchronization with abnormal gamma frequency (30-80 Hz), which are hardly compatible with good sensory and cognitive functioning, especially with respect to the working memory and the perceptual binding.
It is believed that the cortical electrical frequency, named ‘oscillation range’, derives from the synchronisation of interneuronal activity peaks and has a fundamental role in basic cognitive functions, such as attention and sensory processing. Deficit of the gamma oscillation has been associated with some core symptoms of schizophrenia and intellectual and relational developmental disorder. This deficit seems to remain resistant to treatment. This association appears to be mediated by a defect of the balance between the excitatory and inhibitory pulses (E/I) and by dysfunctions of the GABAergic signaling, especially at the level of rapid spike parvalbumin positive interneurons.
Similar abnormalities in the gamma oscillation may indicate the presence of alteration in neuronal circuits common to several neurodevelopmental disorders and may represent a novel biomarker for early and specific treatment.
Recently, a group of researchers from the Department of Psychiatry at the University of Pennsylvania-Philadelphia investigated the relationship between the timing range, E/I signaling, and behavioral phenotypes in mice with reduced expression of the NR1 subunit of the NMDA receptor. In these animals the constitutional hypofunction of NMDA resulted in a loss of E/I balance, an increase in the excitability of pyramidal cells, and a selective depletion of parvalbumin-positive interneurons. The changes in the cellular E/I signaling of were related to certain target behaviours. In fact, the E/I balance alteration was associated with deficits in the signal to noise ratio of acoustically evoked gamma. Abnormalities of gamma frequency predicted deficit of spatial working memory and capacity of social choice. Baclofen, a GABA-B receptor agonist, has improved the E/I balance, has rescaled the gamma signal to noise ratio, and did significantly regressed behavioral deficits.
These data confirm the existence of an easy-to-detect cortical neuronal activity, which may represent a biological marker for preclinical screening and individualized therapies in the near future, for a wide range of psychiatric disorders sharing endophenotypes linked to defects in NMDA receptor signaling.
REFERENCES
- Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010; 42: 1021–1026.
- Gandal MJ, Sisti J, Klook K, Ortinski PI, Leitman V, Liang Y, Thieu T, Anderson R, Pierce RC, Jonak G, Gur RE, Carlson G, Siegel SJ. GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry. 2012 Jul 17;2:e142. doi: 10.1038/tp.2012.69.
- Hamdan FF., Gauthier J., Araki Y., Lin DT., Yoshizawa Y., Higashi K et al. Excess of denovo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 2011; 88: 306–316.
-Saunders JA, Gandal MJ, Roberts TP, Siegel SJ. NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders. Behav Brain Res. 2012 Jul 5;234(2):233-237.