Altered excitatory and inhibitory neocortical circuitry leads to increased convulsive severity after pentylenetetrazol injection in an animal model of schizencephaly, but not of microgyria.

OBJECTIVE: Malformations of the polymicrogyria spectrum can be mimicked in rodents through neonatal transcranial focal cortical freeze lesions. The animals presenting the malformations present both altered synaptic events and epileptiform activity in the vicinity of the microgyrus, but the comprehension of their contribution to increased predisposition or severity of seizures require further studies. METHODS: In order to investigate these issues, we induced both microgyria and schizencephaly in 57 mice and evaluated: their convulsive susceptibility and severity after pentyleneterazol (PTZ) treatment, the quantification of their symmetric and asymmetric synapses, the morphology of their dendritic arbors, and the content of modulators of synaptogenesis, such as SPARC, gephyrin and GAP-43 within the adjacent visual cortex. RESULTS: Our results have shown that only schizencephalic animals present increased convulsive severity. Nevertheless, both microgyric and schizencephalic cortices present increased synapse number and dendritic complexity of layer IV and layer V-located neurons. Specifically, the microgyric cortex presented reduced inhibitory synapses, while the schizencephalic cortex presented increased excitatory synapses. This altered synapse number is correlated with decreased content of both the anti-synaptogenic factor SPARC and the inhibitory postsynaptic organizer gephyrin in both malformed groups. Besides, GAP-43 content and dendritic spines number are enhanced exclusively in schizencephalic cortices. SIGNIFICANCE: In conclusion, our study supports the hypothesis that the sum of synaptic alterations drives to convulsive aggravation in animals with schizencephaly, but not microgyria after PTZ treatment. These findings reveal that different malformations of cortical development should trigger epilepsy via different mechanisms, requiring further studies for development of specific therapeutic interventions.

Differential expression of glutamatergic receptor subunits in the hippocampus in carioca high- and low-conditioned freezing rats.

Anxiety is an emotional state that affects the quality of human life. Several neurotransmitters are involved in the regulation of anxiety, including glutamate. The major actions of glutamate are mediated by N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The present study performed a behavioral and neurochemical analysis of Carioca High-conditioned Freezing (CHF) and Carioca Low-conditioned Freezing (CLF) rats compared with control rats. We evaluated thermal nociception, anxiety-like behavior, depressive-like behavior, spatial memory, habituation memory, and the content and localization of different glutamatergic receptor subunits and postsynaptic density-95 (PSD-95), a postsynaptic protein. The CHF group exhibited an anxious-like phenotype, impairments in habituation and spatial memory, and a depressive-like phenotype compared with the control group. In the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA1 subunits and a decrease in the GluN2A subunit of glutamatergic receptors. The CLF group exhibited a less anxious-like phenotype, hyperlocomotion and habituation impairments. Also, CLF animals, presented, in the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA2 subunits and a decrease in the GluN2B subunit. These results suggest that the differential composition of NMDAR and AMPAR subunits may be related to the modulation of different phenotypes in CHF and CLF rats, which may help identify new targets for therapeutic interventions for anxiety disorders and other comorbidities.