Neonatal Freeze Lesion‐Induced Cortical Malformation Alters Hippocampal Gene Expression and Leads to Persistent Cognitive and Emotional Deficits in Adult Male Wistar Rats

Cortical malformations, including microgyria, are often associated with neurodevelopmental comorbidities such as epilepsy and cognitive impairments in humans. To investigate how early cortical disruption leads to persistent behavioral impairments, we employed a neonatal neocortical focal freeze lesion (FFL) model of polymicrogyria in male Wistar rats. Unilateral cortical lesions were induced at postnatal day 0 (P0), and molecular changes in hippocampal gene expression (glutamatergic signaling: Grin1, Grin2a, Grin2b, Gria1, Gria2; neuroinflammation: Nlrp3, Il1b, Il1rn; glial markers: Gfap, Aif1; neurotrophic factors: Bdnf, Fgf2) were analyzed at P21. Behavioral outcomes, including locomotor activity, exploratory behavior, anxiety-like behavior, social interaction, and recognition memory, were assessed in adulthood (P70-P90). Neonatal cortical lesions induced subregion-specific alterations in hippocampal gene expression: Grin2b and Gria1 expression decreased in the ipsilateral dorsal hippocampus, while Grin2a, Bdnf, and Fgf2 increased in the contralateral ventral hippocampus. These molecular changes were associated with subsequent cognitive deficits (impaired recognition memory) and emotional dysregulation (heightened anxiety-like behavior) in adult rats, alongside reduced exploratory activity. Basic motor functions and sociability remained unaffected, and seizure susceptibility (assessed via maximal electroshock threshold) was unchanged, highlighting the specificity of the observed impairments. Our findings suggest a potential mechanistic link between early-life cortical malformations with microgyrus formation, dysregulation of hippocampal synaptic plasticity and neurotrophic signaling, and persistent neurobehavioral deficits. These results underscore the translational relevance of the freeze lesion model for studying the neurodevelopmental trajectory of cortical malformation-related comorbidities.