Neuronal migration disorders: Heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex

Abstract

Neuronal migration disorders have been involved in various pathologies, including epilepsy, but the properties of the neural networks underlying disorders have not been determined. In the present study, patch clamp recordings were made from intrahippocampal heterotopic as well as from neocortical and hippocampal neurons from brain slices of rats with prenatally methylazoxymethanol-induced cortical malformation. We report that heterotopic neurons have morphometrical parameters and cellular properties of neocortical supragranular neurons and are integrated in both neocortical and hippocampal networks. Thus, stimulation of the white matter induces both antidromic and orthodromic response in heterotopic and neocortical neurons. Stimulation of hippocampal afferents evokes a monosynaptic response in the majority of heterotopic neurons and a polysynaptic allor-none epileptiform burst in the presence of bicuculline to block ␥-aminobutyric acid type A inhibition. Furthermore, hippocampal paroxysmal activity generated by bath application of bicuculline can spread directly to the neocortex via the heterotopia in methylazoxymethanol-treated but not in naive rats. We conclude that heterotopias form a functional bridge between the limbic system and the neocortex, providing a substrate for pathological conditions. Migration of young postmitotic neurons from the ventricular zone to the cortical plate where they differentiate is a key event in cortical development. Neuronal migration disorders lead neurons to differentiate in an abnormal or heterotopic position (1). Periventricular and subcortical heterotopias long have been described in the brain of patients suffering from epilepsy (2-6). Moreover, discrete intracortical heterotopias also have been described in the brains of patients suffering from dyslexia (7) and schizophrenia (8). Together, these data suggest that neuronal migration disorders may constitute a morphological basis for these pathologies.Despite their importance for the understanding of the physiopathological mechanisms of these disorders, the cellular properties and connections of heterotopic neurons are known poorly. In the present study, we have used the prenatal methylazoxymethanol (MAM) model that is associated with microcephaly (9, 10) and cortical disorganization with periventricular and intrahippocampal heterotopias (11-13). We report that intrahippocampal neocortical heterotopic neurons have bi-directional monosynaptic connections with the neocortex and are integrated in the hippocampal circuitry. They therefore provide a direct aberrant link between the hippocampus and the neocortex and a basis for disorders associated with cortical malformation. As an example for this, we report that paroxysmal activity generated in the hippocampus can directly propagate to the neocortex via the heterotopia. MATERIALS AND METHODSAnimals. Pregnant Wistar rats were injected i.p. with 25 mg͞kg of MAM (Sigma) dissolved in saline at embryonic day 14 (first gestation day as embryonic day 0). After normal delivery, r...

Abnormal Network Activity in a Targeted Genetic Model of Human Double Cortex

“…Similar to these observations, previous studies on MAM, x-ray-irradiated, and TISH rats depicted the presence of functional cortical-heterotopia connections (for review, see Chevassus-Au-Louis et al, 1999), even when ectopic cortical neurons localize within the hippocampus (Chevassus-Au-Louis et al, 1998); these connections provide a morphological substrate to integrate heterotopia and experimental cortex within the same network. One of the more interesting observations reported here is the activation of experimental cortex earlier than ectopic neurons, indicating that heterotopias are followers rather than initiation centers, in agreement with earlier studies on intrahippocampal heterotopia in MAM rats (Chevassus-Au-Louis et al, 1998) or the band heterotopia of TISH rats (Chen et al, 2000). The band heterotopia may rather act as a relay-projection center to subcortical structures so that activity patterns generated in the experimental L2/3-heterotopic loop would easily be propagated to other brain areas and contribute to neurologic manifestations such as epilepsy and mental retardation.…”

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

“…It is not known, however, whether nucleic acid methylation underlies MAM's preferential effects on neurons, especially cortical neurons (Cattabeni and Di Luca 1997;Chevassus-Au-Louis et al 1998;Haddad et al 1972;Singh 1980). The DNA methylation may regulate the expression of reelin and GAD 67 , genes that are downregulated in the cortex in schizophrenia (Dong et al 2005;Tremolizzo et al 2002).…”

“…Exposure to MAM on or prior to E15 leads to abnormalities in corticocortical synaptic transmission (Chevassus-Au-Louis et al 1998), striatal hyperdopaminergia with increased responsiveness to psychostimulants (Archer et al 1988;Watanabe et al 1995), and cognitive and sensorimotor gating deficits (Mohammed et al 1986;Talamini et al 2000). While these abnormalities are relevant to a number of developmental brain disorders (Cattabeni and Di Luca 1997;Chevassus-Au-Louis et al 1998;Coyle et al 1984), their validity for modeling schizophrenia is limited due to the microcephaly produced by MAM exposure on or before E15 (Dambska et al 1982;Jongen-Relo et al 2004;Kabat et al 1985;Singh 1980). To address this limitation, we administered MAM on E17 (Grace and Moore 1998;Moore et al 2001).…”

Pilocarpine-Induced Seizure Susceptibility in Rats Following Prenatal Methylazoxymethanol Treatment

“…6) Heterotopic neurons in the MAM model lack potassium channels and exhibit burster firing properties 7,8) and heterotopia received abundant GABAergic innervations in the MAM exposed rats. 9) Heterotopic CA1 pyramidal neurons appear to have atypical electrophysiological and morphological characteristics 10) and may form abnormal connections with neocortical regions. 11) Although it is well established that these models mimic the structural aspects of human early-onset epilepsy syndrome, there were few behavioral changes regarding spontaneous and recurrent seizures in the MAM rats.…”