Malformations of cortical development frequently underlie drug-resistant epilepsy, yet little is known about how malformed cortical networks terminate epileptiform activity. In acute cortical slices from juvenile male Wistar rats with a focal freeze lesion, we compared the microgyrus and paramicrogyral zone during low-Mg2+/gabazine-induced epileptiform activity. Discharges terminated earlier in the microgyrus than in the paramicrogyral zone (median, 268 vs. 496 ms), without detectable regional differences in peak discharge-associated inward current or the weighted decay time constant of extracellular K+ transients. In separate voltage-clamp recordings, the transition to a slow post-discharge outward current occurred earlier in microgyral neurons, and the current peaked sooner and showed a smaller normalized late component. GABAB receptor blockade with CGP-55845 prolonged discharges and preferentially disrupted the faster post-peak current decay in the microgyrus. Intracellular QX-314, used to probe a postsynaptic component, eliminated detectable regional differences in outward-current kinetics. Gabbr1 and Gabbr2 mRNA abundance did not differ detectably between the microgyrus and contralateral cortex. Overall, the findings support a postsynaptic GABAB-dependent contribution to earlier epileptiform discharge termination within the microgyrus. More broadly, malformation-associated reorganization includes local negative-feedback processes that constrain pathological network persistence alongside mechanisms that promote hyperexcitability.

Metabolic reprogramming of astrocytes and microglia is considered a significant component of epileptogenesis, associated with the development of neuronal network hyperexcitability, neuroinflammation, and oxidative stress. This review analyzes key mechanisms of glial dysfunction, such as the shift toward aerobic glycolysis (the Warburg effect), mitochondrial disturbances, and generation of reactive oxygen species. These processes are regulated by the Wnt/GSK3β and mTOR signaling cascades, forming a vicious cycle of energy deficit, NLRP3 inflammasome activation, and excitotoxicity. Particular attention is given to strategies for correcting glial metabolism. The greatest therapeutic interest lies in systemic approaches that correct metabolism (ketogenic diet, GLP-1 and PPAR receptor agonists) and high-precision technologies for selective modulation of glial functions (RNA therapy, nanodelivery). Targeted intervention in glial metabolism opens ways to the development of anti-epileptogenic drugs capable of modifying the disease course rather than merely alleviating the symptoms. However, translation of these approaches into clinical practice requires clarification of therapeutic windows for the intervention and development of biomarkers of glial status.

Epilepsy is a severe chronic condition that remains pharmacoresistant in approximately 30

GLP-1 receptor (GLP-1R) agonists are increasingly investigated in epilepsy, but antiseizure activity, neuroprotection, and disease modification are distinct therapeutic claims. This critical narrative review with structured evidence mapping separates these claims across 21 preclinical primary publications and eight human studies identified through 6 August 2026. Selected GLP-1R-related interventions show antiseizure and anti-kindling signals, but effects vary across compounds, models, treatment timing, and seizure types; null and pro-seizure findings in absence epilepsy preclude a uniform class-wide antiseizure effect, and concurrent anti-kindling does not establish antiepileptogenesis. Neuroprotective evidence is broader, although direct neuronal or tissue preservation is demonstrated only in selected studies; many findings remain biomarker-based, and seizure reduction may itself lessen downstream injury. Evidence for durable disease modification remains suggestive rather than established. Causal support is strongest at the receptor level, whereas most downstream synaptic, inflammatory, glial, oxidative, and mitochondrial evidence remains associative. Semaglutide has high translational relevance but remains directly under-tested in epilepsy, and human evidence is predominantly observational or safety-oriented and does not establish therapeutic epilepsy efficacy. Progress requires chronic epilepsy studies with longitudinal EEG/video-EEG and baseline seizure burden, post-insult designs controlling initial-insult severity and assessing persistence after withdrawal, and linked pharmacokinetic, target-engagement, and causal mechanistic testing.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) suppresses neuroinflammation and may interrupt epileptogenesis. We tested whether early intervention with the PPARα agonist fenofibrate exerts disease-modifying effects in the chronic phase of the lithium-pilocarpine model of temporal lobe epilepsy. Male Wistar rats received fenofibrate (100 mg/kg, i.p., daily for 15 days) initiated 1 h after status epilepticus. Outcomes were assessed 1-3 months later. Fenofibrate significantly attenuated neuronal loss in the dorsal CA1 subfield and ventral hilus of the hippocampus, partially reduced astrogliosis in the hilus, and decreased the proportion of amoeboid microglia in CA1. Behaviorally, fenofibrate prevented the TLE-induced reduction in risk-assessment exploration in the elevated plus maze, without affecting general locomotion or anxiety. Critically, fenofibrate did not alter the incidence of spontaneous recurrent seizures, interictal spike frequency, or the pathological reduction in delta and theta EEG power. It also failed to normalize the aberrant cortical response to pentylenetetrazol or reduce seizure severity. These findings demonstrate that early PPARα activation confers region-restricted neuroprotection and modest behavioral benefit, but does not suppress the core pathophysiological features of chronic epilepsy. The results dissociate neuroprotection from antiepileptogenesis and caution against assuming that anti-inflammatory interventions alone are sufficient for disease modification in temporal lobe epilepsy.

Microglial activation and neuroinflammation are recognized as key drivers of synaptic dysfunction in temporal lobe epilepsy (TLE), yet the causal mechanisms linking specific microglial phenotypes to neuronal hyperexcitability remain poorly understood, and clinically viable therapeutic strategies to modulate these processes are urgently needed. Using the lithium-pilocarpine model in young male rats (P21-P28), we demonstrate that a 7-day minocycline treatment (100 → 50 mg/kg, i.p.), initiated immediately following status epilepticus, induces robust and selective microglial morphological remodeling. Quantitative morphometric analysis of Iba1+ cells revealed a significant shift from activated amoeboid morphology to surveillant ramified phenotypes, without altering microglial density in hippocampal CA1 regions. This structural reorganization correlated with complete functional recovery: electrophysiological recordings showed full restoration of NMDA receptor-dependent long-term potentiation and rescue of NMDAR-mediated currents during high-frequency stimulation. Importantly, these synaptic improvements occurred independently of neuroprotection, as Nissl staining confirmed unchanged neuronal survival in CA1/CA3 subfields. Behavioral assessments at P27 demonstrated significant attenuation of epilepsy-associated anxiety-like behaviors, including reduced self-grooming and normalized exploratory activity in the open field test. Notably, minocycline treatment also attenuated reactive astrogliosis, suggesting coordinated modulation of neuroinflammatory cascades. Our findings demonstrate that short-term minocycline administration induces a structural and functional reprogramming of microglia, which is sufficient to restore hippocampal synaptic plasticity and reduce anxiety in a rat model of TLE. This highlights microglial morphological plasticity as a critical therapeutic target for counteracting epileptogenesis.

Febrile seizures (FS), the most common early-childhood neurological emergency, have a poorly understood impact on the maturing glutamatergic system. We present a detailed spatiotemporal analysis of transcriptional dynamics of key glutamatergic components during a critical postnatal window. Using a hyperthermia-induced FS model in rats at postnatal day 10, we measured mRNA levels of ionotropic (NMDA, AMPA) subunits, metabotropic glutamate receptor (mGluR) groups I-III, glutamate transporters (Slc1a1-3), and glutamine synthetase (Glul) across the dorsal/ventral hippocampus, temporal and medial prefrontal cortices at P14, P21, and P50. For selected targets (GluN2A/2B, GluA1/2, EAAT2), protein abundance was analyzed by Western blotting to test how closely transcriptional changes are reflected at the protein level. We identified robust region- and age-specific developmental trajectories for all targets, including the expected maturational shift in NMDA receptor subunits. FS disrupted these programs, causing widespread downregulation of NMDA and AMPA receptor subunits, mGluRs, and astrocytic transporters in the dorsal hippocampus and temporal cortex at P14. Importantly, FS prevented the normal developmental increase in the Grin2a/Grin2b mRNA ratio in the dorsal hippocampus at P21. Notably, protein abundance for selected targets did not mirror transcriptional changes at the examined time points, suggesting post-transcriptional buffering or delayed translation. This mismatch suggests that transcriptional changes may precede detectable proteomic alterations during circuit maturation, although alternative explanations, such as delayed translation or post-translational regulation, cannot be excluded. Our findings identify candidate transcriptional correlates that may contribute to long-term neurocognitive vulnerability, and highlight the potential importance of timing when targeting glutamatergic pathways for neuroprotection.

The mechanisms underlying the generation and termination of epileptic discharges remain incompletely understood. This study investigates the role of KCa3.1 (KCNN4) channels in modulating epileptiform activity in the deep layers of the entorhinal cortex using two in vitro models: short-lasting late recurrent discharges (LRDs) and prolonged tonic-clonic seizure-like events (SLEs). Whole-cell patch-clamp recordings in rodent brain slices revealed that blocking KCa3.1 channels with TRAM-34 increased neuronal excitability and firing frequency, enabling sustained firing at higher depolarizing currents. In the LRD model, TRAM-34 had no effect on the frequency or duration of spontaneously generated LRDs, likely due to the low intrinsic expression of KCa3.1 channels in the entorhinal cortex. However, NS-309, a positive modulator of KCa3.1 and SK channels, reduced LRD duration, while TRAM-34 prolonged LRDs induced by extracellular stimulation. In the SLE model, TRAM-34 increased SLE frequency and enhanced glutamatergic activity at SLE onset, indicating a more pronounced role of KCa3.1 channels during intense epileptiform activity. To address the function of KCa3.1 channels in glutamatergic neurons, we specifically overexpressed KCNN4 in these cells using a viral vector. Although overexpression did not abolish LRD generation, its duration and magnitude were significantly reduced, mirroring the effects of NS-309. These results demonstrate that the contribution of KCa3.1 channels to epileptiform activity depends on its temporal pattern, with minimal influence on short LRDs but greater effects on robust glutamatergic activity at SLE onset. Thus, KCa3.1 upregulation provides feedback mechanisms for the premature termination of epileptiform discharges, suggesting KCa3.1 channels as potential therapeutic targets.

Disruptions in cerebral cortex development during early ontogenesis often lead to pharmacoresistant epilepsy and mental disorders. One such disruption is focal cortical dysplasia (FCD), which can be modeled in experimental animals by inducing cryogenic injury to the neocortex on the first day after birth. FCD is frequently associated with the development of epilepsy and behavioral impairments, such as deficits in learning, memory, and social interaction. These effects may be more pronounced when the brain is exposed to additional challenges, such as the combination of FCD with neonatal febrile seizures (FS). However, the specific characteristics of behavioral impairments in this combined pathology remain poorly understood. This study aimed to investigate behavioral impairments in adult male Wistar rats with FCD who had experienced FS. FCD was induced in rat pups on the first day of life (P0) by localized freezing of the somatosensory cortex. On the 10th day of life (P10), FS were triggered in the rat pups through hyperthermia (exposure to warm air) for 30 minutes. Only animals with FS lasting at least 15 minutes were included in the study. The control group consisted of sham-operated rat pups that were separated from their mother for 30 minutes at P10 without exposure to heat. At 2–2.5 months of age, the animals’ behavior was evaluated using the following tests: Open Field, Elevated Plus Maze, Social Interaction Test, and Spontaneous Alternation Test in the Y-Maze. The results revealed that the combination of FCD and FS in early life led to increased social activity and alterations in exploratory behavior and anxiety levels in adult rats. These findings suggest that the combined pathology selectively affects behavioral functions, potentially due to the reorganization of neural networks in the brain. The study expands our understanding of the consequences of FCD and FS on brain function development and highlights the need for further research into the mechanisms underlying these changes. This work may contribute to the development of new therapeutic strategies for patients with similar conditions.

Febrile seizures (FS) in early childhood can lead to the development of epilepsy; however, in most cases, they resolve without consequences. The neurophysiological mechanisms that protect the brain from the effects of FS remain poorly understood. It is also known that the risk of epilepsy significantly increases if a child has congenital abnormalities in the structure of the cerebral cortex. In this study, we examined functional changes in the hippocampus of young rats subjected to FS on the 10th postnatal day (P10) with freezing-induced focal cortical dysplasia (FCD) on P0. Experiments were conducted on three groups of animals: (1) control group (Ctrl)—rats without FS and FCD; (2) FS group—rats subjected to hyperthermia-induced FS on P10; (3) FS+FCD group—rats with cortical freezing on P0 and FS on P10. Using recordings of local synaptic potentials in the CA1 region of the hippocampus, we found that FS led to significant changes in synaptic transmission. In the FS group, there was an increase in the threshold for population spike generation, a decrease in the synaptic transmission efficacy ratio, and an increase in the paired-pulse ratio. These changes indicate reduced activity of CA3-CA1 glutamatergic synapses, which may represent a compensatory response preventing epileptogenesis. However, in the FS+FCD group, such compensatory changes were absent: synaptic transmission parameters did not differ from those in the control group. This suggests that FCD impedes the activation of protective mechanisms in the hippocampus in response to FS. Thus, the presence of cortical dysplasia may increase the risk of epilepsy following FS by blocking natural compensatory processes. Our results highlight the importance of studying the interaction between congenital cortical developmental abnormalities and the consequences of FS for understanding the mechanisms of epileptogenesis.

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K+]o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K+] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K+]o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K+-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target.

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy; however, the mechanisms underlying hyperexcitability in the affected cortical regions remain poorly understood. In this study, we employed a freeze-induced neocortical malformation model in rats to investigate the electrophysiological properties of pyramidal neurons surrounding the microgyrus and to evaluate changes in synaptic transmission. Using whole-cell patch-clamp recordings, we analyzed passive and active membrane properties, synaptic responses, and epileptiform activity in brain slices from rats with FCD and sham-operated controls. Our results revealed that while the intrinsic biophysical properties of neurons remained largely unchanged, the summation of excitatory and inhibitory inputs was significantly enhanced. Notably, the balance of inhibitory and excitatory synaptic currents was shifted toward excitation, making the perilesional cortex more susceptible to seizure generation. In a model of epileptiform activity induced by GABAA receptor blockade and reduced Mg2+ concentration, we observed early ictal activity originating in the microgyrus and spreading to adjacent regions. These findings demonstrate that synaptic perturbations, rather than alterations in intrinsic neuronal properties, are the primary drivers of hyperexcitability in this model. Our study highlights the importance of synaptic dysregulation in FCD-related epilepsy and suggests that targeting synaptic transmission may offer a promising therapeutic strategy for controlling seizures in patients with cortical malformations.

Epilepsy is one of the most common chronic neurological disorders, characterized by spontaneous recurrent seizures that cause substantial disability worldwide [...]

Febrile seizures (FS) are a common childhood neurological event associated with an increased risk of long-term cognitive and emotional deficits, though the precise mechanisms remain elusive. Using a rat model, we investigated the long-term effects of FS induced on postnatal day 10, assessing outcomes in young adulthood (P45-55). We report region-specific neuronal loss in the hippocampus, more extensive in the ventral segment. Molecular analysis revealed a broad downregulation of genes encoding ionotropic and metabotropic glutamate receptors and excitatory amino acid transporters. These alterations were most severe and persistent in the ventral hippocampus and medial prefrontal cortex. Behaviorally, rats with neonatal FS exhibited a hyperanxious phenotype, characterized by reduced locomotor and exploratory activity and impaired habituation to a novel environment. In contrast, spatial working memory and social behavior remained intact. Our results provide the first comprehensive evidence that neonatal FS trigger long-term, region-specific disruptions of the glutamatergic system within hippocampal–prefrontal circuits. These findings identify vulnerable molecular targets and precise neurobiological mechanisms that may underlie the heightened risk of anxiety-related disorders following early-life FS, suggesting new avenues for therapeutic intervention.

In the central Sikhote-Alin Mountains, tigers prey mainly on underyearlings and adult female wild boars (67–74% of the total number of this species’ prey). In key plots (≥10–15 km2) in the Sikhote-Alin Nature Reserve, (a) wild boar encounters and their tracks in the network of routes were recorded; (b) wild boar snow tracking was performed; and (c) tiger encounters and snow tracking were registered (114 episodes). We obtained 16 movement patterns of wild boar groups using snow tracking. Snow tracking of each wild boar group took 6 to 23 days. Many maternal groups occupied a position central in relation to other accompanying groups (up to 8) and individuals (up to 15) moving in the vicinity, usually over an area (1.5–9.4 km2 or more) that was 1.1–2.2 or more times larger than the area of the maternal group under normal conditions. Such a dynamic organization of associations that serves as a kind of pre-adaptation to the probable appearance of a predator revealed the effectiveness against the tiger both randomly searching for prey and tracking it along a trail. The number of tiger attacks on accompanying wild boars temporarily separated from the parental group was nearly three times (p 0.05) as high as the number of attacks by the predator on maternal groups in key plots. In the relationships between the predator and prey species, (a) the location of the habitats of the maternal wild boar groups matters as well, in snowy winters also of compact camps, all usually at a distance from regular tiger routes; (b) disturbed wild boars broadened the search areas, at tiger pursuits and attacks they also changed the site; (c) the tuskers, the male wild boars that accompany maternal groups, often “disguise” these groups by moving to the side of the most probable tiger appearance.

Prenatal hyperhomocysteinemia (HCY) is associated with neurodevelopmental deficits, yet its long-term impact on hippocampal synaptic function remains poorly understood. This study examines the effects of moderate maternal HCY on excitatory synaptic transmission in the CA1 region of the dorsal hippocampus in rat offspring at juvenile (P21) and adult (P90) stages. Using field postsynaptic potential (fPSP) recordings, electron microscopy, and Western blot analysis, we observed a significant age-dependent decline in the efficiency of excitatory synaptic transmission in HCY-exposed rats. Electron microscopy revealed structural alterations, including synaptic vesicle agglutination in the stratum radiatum, suggesting impaired neurotransmitter release. Additionally, a significant reduction in pyramidal neuron density was observed in the CA1 region, although seizure susceptibility remained unchanged. Western blot analysis showed altered expression of Synapsin I, indicating presynaptic dysfunction. These findings suggest that moderate prenatal HCY leads to persistent deficits in synaptic transmission and structural integrity, potentially contributing to cognitive impairments in adulthood. Our results highlight the importance of maternal homocysteine levels in shaping hippocampal function and could offer insights into neurodevelopmental disorders associated with metabolic disturbances.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are strongly involved in the regulation of neuronal excitability, with their precise role being determined by their subcellular localization and interaction with other ion channels and transporters. Their role in causing epileptic seizures is not fully understood. Using whole-cell patch-clamp recordings of rat brain slices, we show that HCN channels constitute a substantial fraction of the membrane conductance of deep entorhinal principal neurons. Using the 4-aminopyridine model of epileptic seizures in vitro, we show that HCN channel blockade with ZD-7288 increases the frequency of seizure-like events (SLEs) and alters the time course of afterhyperpolarization after SLEs (post-SLE AHP), promoting its faster onset and making it more transient. Simultaneous whole-cell patch-clamp and K+ ion-selective electrode recordings revealed that the time course of changes in neuronal membrane potential and extracellular K+ concentration after SLEs in the presence of ZD-7288 differed from that in the control, which can be explained by altered Na/K-ATPase [sodium-potassium adenosine triphosphatase (sodium-potassium pump)] activity after SLEs. To confirm this hypothesis, we demonstrated the ouabain sensitivity of post-SLE AHP and showed that loading neurons with high intracellular Na+ concentration prevented the effect of HCN channel blockade on post-SLE AHP. Taken together, the results obtained suggest that during post-SLE AHP, the influx of Na+ through HCN channels helps to maintain Na/K-ATPase hyperactivity, resulting in the longer pauses between SLEs. Mathematical modelling confirmed the feasibility of the proposed mechanism. Such an interplay between Na/K-ATPase and HCN channels may be crucial for the regulation of seizure termination in epilepsy. KEY POINTS: HCN channels constitute a significant fraction of the resting membrane conductance of deep entorhinal principal neurons. HCN channels modulate the seizure-like events (SLEs) in the entorhinal cortex. The blockade of HCN channels increases the frequency of SLEs and reduces the duration of the afterhyperpolarization that follows them. The results suggest that HCN channels affect intracellular sodium ion concentration dynamics, prolonging the activity of the Na/K-ATPase [sodium-potassium adenosine triphosphatase (sodium-potassium) pump] after SLEs, which in turn results in longer pauses between them.

The search for novel compounds with anticonvulsant properties remains a key focus in neuropharmacology. Recently, the diazepine-benzimidazole derivative, DAB-19, has emerged as a promising candidate due to its demonstrated anxiolytic and analgesic effects. In this study, we investigate the mechanisms underlying DAB-19’s activity, focusing on its impact on glutamatergic transmission, a key target in the pathophysiology of various central nervous system disorders. Intriguingly, while DAB-19 suppressed evoked glutamatergic transmission in rat brain slices, it simultaneously enhanced spontaneous neurotransmission. Further experiments on glutamatergic neuromuscular synapses in fly larvae revealed two distinct mechanisms: calcium-dependent potentiation of glutamate release and inhibition of spike propagation via blockade of voltage-gated sodium channels. The latter effect was directly confirmed in rat brain neurons. Given its action on sodium channels, we tested DAB-19 in the pentylenetetrazole model, where it delayed seizure onset but did not prevent seizures. These findings position DAB-19 as a multifaceted compound with significant therapeutic potential.

Temporal lobe epilepsy (TLE) remains pharmacoresistant in 30–40% of patients. Peroxisome proliferator-activated receptor alpha (PPARα) agonists like fenofibrate exhibit anti-inflammatory and neuroprotective properties, but their region-specific effects during epileptogenesis and on behavioral comorbidities are unknown. We investigated fenofibrate (100 mg/kg, 7 days) in the lithium-pilocarpine rat model during the latent phase. Fenofibrate (1) reduced anxiety-like behaviors and improved exploratory deficits; (2) decreased plasma short-chain fatty acids (butyric, pentanoic, hexanoic acids); (3) exerted region-specific modulation of glutamate receptors: restored N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit gene expression in temporal cortex but failed to reverse and further exacerbated the downregulation of AMPAR subunits in the dorsal hippocampus; (4) prevented the upregulation of cortical neuroinflammation markers (reduced Nlrp3, Il1rn); and (5) enhanced the A2 astrocyte marker Ptx3 in the hippocampus while reducing the M2 microglial marker Arg1 in the temporal cortex. No effects on astrogliosis (Gfap), microgliosis (Aif1), or trophic factors (Bdnf, Tgfb1) were observed. This first comprehensive study demonstrates that fenofibrate differentially modulates neuroinflammation and synaptic plasticity across brain regions during epileptogenesis, providing behavioral benefits but highlighting potential hippocampal drawbacks. Its PPARα-mediated actions support further investigation as a complementary strategy for TLE, pending optimization of dosing/timing to mitigate regional disparities.

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.