Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism

Abstract

The prefrontal cortex has been extensively implicated in autism to explain defi cits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to signifi cantly more neighbouring neurons than in controls. These excitatory connections are more plastic displaying enhanced long-term potentiation of the strength of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms. We propose that a number of defi cits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyperfunctional prefrontal cortex.

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

“…In particular, the numbers of action potentials generated by current steps were lower (Fig. 1C), which confirms a previously reported finding in early postnatal animals (Rinaldi et al, 2008a). This deficit was not caused by a general impairment in the ability of neurons to produce action potentials, since single-spike properties, such as rheobase and spike shape, were unchanged.…”

“…At a physiological level, previous work has shown that neocortical pyramidal neurons of 2-week-old VPA-exposed animals exhibit two strong abnormalities: impaired intrinsic excitability and excessive NMDA currents (Rinaldi et al, , 2008a. Using whole-cell patch recordings from medial prefrontal cortex (mPFC), we confirmed these findings and went on to trace their postnatal time course.…”

“…The AMPA result is somewhat different from what has been reported for layer 5 pyramidal neurons in 2-week-old animals (Rinaldi et al, 2008a). We will address this discrepancy in the Discussion.…”

“…Abnormalities in excitatory synaptic transmission have been reported in 2-week-old VPA animals (Rinaldi et al, , 2008a. We examined this issue by evoking monosynaptic currents with extracellular stimulation and calculating the ratio of NMDAmediated to AMPA-mediated currents at proximal synapses ( Fig.…”

The Strategies of the Genes: Genomic Conflicts, Attachment Theory, and Development of the Social Brain

“…The existence and structure of brain-specific imprinted-gene network should have important implications for pharmacological interventions; for example, of the 11 genes most-highly altered in expression from treatment of mice with the mood-stabilizer drug valproic acid (Chetcuti et al 2006), two are imprinted (Peg3 and Sfmbt2), one is predicted to be imprinted (Zic1) (Luedi et al 2007), one interacts directly with the imprinted gene Wt1 (Par-4) (Richard et al 2001), and one (Kcna1) interacts directly with Cntnap2 (Strauss et al 2006). Such a striking concentration of imprinted-gene related expression changes is consistent with the molecular function of valproic acid as a histone deacetylase inhibitor, an agent that exhibits differential epigenetic effects on imprinted genes (e. g., Baqir and Smith 2006); moreover, valproic acid during human or rodent pregnancy is a highly-penetrant cause of autism in offspring (Rinaldi et al 2008;Dufour-Rainfray et al 2010), and valproic acid partially restores levels of MeCP2 in a mouse model of Rett syndrome (Vecsler et al 2010). Might such epigenetic treatments exert their effects though canalizing or decanalizing neurological-pathway functions of interacting imprinted genes?…”