Early valproic acid exposure alters functional organization in the primary visual cortex

Abstract

Epilepsy is one of the most common neurologic disorders and affects 0.5 to 1% of pregnant women. The use of antiepileptic drugs, which is usually continued throughout pregnancy, can cause in offspring mild to severe sensory deficits. Neuronal selectivity to stimulus orientation is a basic functional property of the visual cortex that is crucial for perception of shapes and borders. Here we investigate the effects of early exposure to valproic acid (Val) and levetiracetam (Lev), commonly used antiepileptic drugs, on the development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets pups were exposed to Val (200 mg/kg), Lev (100 mg/kg) or saline every other day between postnatal day (P) 10 and P30, a period roughly equivalent to the third trimester of human gestation. Optical imaging of intrinsic signals or single-unit recordings were examined at P42–P84, when orientation selectivity in the ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in Val-but not Lev- or saline-treated animals. Moreover, single-unit recordings revealed that early Val treatment also reduced orientation selectivity at the cellular level. These findings indicate that Val exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in fetal anticonvulsant syndrome.

Targeted Labeling of Neurons in a Specific Functional Micro-domain of the Neocortex by Combining Intrinsic Signal and Two-photon Imaging

“…Merging intrinsic signal optical imaging with two-photon microscopy offers the possibility of determining which synapses and cells contribute to the micro-domain of any functional map, whether neuronal selectivity correlates with the location of the neuron in a functional map, and the neuronal circuit components that change with visual experience 7 or the application of clinically therapeutic drugs 18 .…”

Sensory and Motor Characterization in the Postnatal Valproate Rat Model of Autism

“…During this early rodent post-natal period there is also a high degree of synaptogenesis and refinement of neurological connections, which is dependent on a balance between cellular excitation and inhibition [47]. Since valproate enhances inhibitory GABAergic activity [48, 49], it has the potential to disrupt brain development during this period.…”

Sodium valproate exposure during the brain growth spurt transiently impairs spatial learning in prepubertal rats

“…While the mechanisms of action of VPA are not completely understood, there is a consensus that this anticonvulsant enhances GABAergic activity, suppresses NMDA and voltage-dependent sodium channels, and inhibits histone deacetylase (Johannessen and Johannessen 2003; Loscher 2002; Phiel et al 2001). These multiple actions of VPA during the brain growth spurt, even if transitory, may disturb the establishment of neuronal circuits leading to impairments in neuronal connectivity and plasticity (Pohl-Guimarães et al 2011). Accordingly, the suppression of synaptic neurotransmission via blockade of NMDA receptors or activation of GABA receptors can trigger massive apoptotic neurodegeneration (Bittigau et al 2003).…”

“…Thus, it is reasonable to suppose that VPA could be delaying the development of such behavioral attributes. Interestingly, in ferrets, VPA exposure during the third trimester equivalent of human gestation postponed the time of natural eye opening in 4 to 5 days (Pohl-Guimarães et al 2011). Mice exposed to a single injection of VPA (400 mg/kg sc) at P14 showed retardation in the maturation of behavioral response in inclined plane test (Wagner et al 2006), while mice exposed to VPA in utero, presented delay in eye opening and nest seeking behavior that were accompanied by reduction in cortical brain-derived neurotrophic factor (BDNF) mRNA expression (Roullet et al 2010).…”

“…Children with valproate syndrome may also present cognitive problems including low verbal intelligence quotient, learning and memory deficits, and autistic spectrum disorder (Ornoy 2009; Vinten et al 2005). While the effects of VPA during the first half of gestation are well known, recent studies have shown that exposure during late gestation may also contribute for the fetal anticonvulsant syndrome phenotype (Kim et al 2011; Meador 2008; Pohl-Guimarães et al 2011). …”