ABSTRACT
Title
Abnormal EEG and memory associative deficit in SNAP-25 heterozygous mice
Authors
A. Donzelli
Graduate School in Pharmacological Sciences
Dept. of Pharmacology, Chemotherapy and medical Toxicology,
Università degli Studi di Milano, Italy
Graduate School in Pharmacological Sciences
Dept. of Pharmacology, Chemotherapy and medical Toxicology,
Università degli Studi di Milano, Italy
Abstract
SNAP-25 is a member of the SNARE protein complex that participates in synaptic vesicle exocytosis. There is increasing evidence that SNAP-25 interacts with various voltage-gated ion channels and negatively controls neuronal calcium responsiveness to depolarization by specifically inhibiting voltage-gated calcium channels (1,2). A dysregulation of calcium dynamics, due to alterations of SNAP-25 expression,+ may thus lead to unbalances of neuronal network activity. In line with this possibility, alterations of SNAP-25 expression have been associated to several neurological diseases, such as schizophrenia, ADHD and epilepsy (3).
On this basis the aim of the present study was to investigate whether the enhanced calcium responsiveness had implications for the neuronal brain network activity. Electroencephalographic recording (EEG) was performed in the cortices of SNAP-25 heterozygous (ET) and age-matched control (WT) mice. Since abnormal EEG can be associated to altered cognitive function (4) different forms of associative memory were also investigated. Finally, we tested the possibility to normalize the abnormal EEG and cognitive impairment through the treatment with different antiepileptic drugs .
Basal EEG, derived from parietal-occipital cortex, was evaluated in freely moving awake mice for 24 hours while the effect of valporate (250 mg/kg), ethosuximide (200 mg/kg), carbamazepine (30 mg/kg) and a Ca++ antagonist nimodipine (10 mg/kg) for 3 hours after treatment. The most active antiepileptic drug was chosen for memory tasks (object recognition to test episodic memory and conditioned taste aversion (CTA) to test visceral memory). Motor integrity was also evaluated in an activity cage for 30 min.
During 24-h recording ET mice showed an EEG characterized by a significant increase of spikes compared to WT mice, reminiscent of an epileptic EEG profile (even if no behavioural seizures were shown). All the drugs blocked spike activity but with different potency (valproate>ethosuximide>carbamazepine>nimodipine). Associative memory was impaired in ET mice compared to WT as shown by the reduced ability to discriminate the familiar from the unfamiliar object and to associate a malaise, induced by subcutaneous treatment with LiCl (63 mg/kg), to a flavored acid solution (HCl 0.008M). Treatment with valporate, given 20 min before each test, fully restored cognitive function in ET mice.
In conclusion, these findings demonstrate that decreased brain levels of SNAP-25 increase brain excitability and impair associative memory. Valproate treatment restored both EEG alterations and memory associative deficit leading to a possible association between SNAP-25 and epilepsy.
1) Verderio C et al (2004) - Neuron vol 41(4):599-610.
2) Pozzi D et al (2008) - Proc Natl Acad Sci USA vol 105(1):323-8.
3) Corradini I et al (2009) - Ann N Y Acad Sci vol 1152:93-9.
4) Shatskikh TN et al (2006) - Epilepsy Behav vol 9(4):549-56.
On this basis the aim of the present study was to investigate whether the enhanced calcium responsiveness had implications for the neuronal brain network activity. Electroencephalographic recording (EEG) was performed in the cortices of SNAP-25 heterozygous (ET) and age-matched control (WT) mice. Since abnormal EEG can be associated to altered cognitive function (4) different forms of associative memory were also investigated. Finally, we tested the possibility to normalize the abnormal EEG and cognitive impairment through the treatment with different antiepileptic drugs .
Basal EEG, derived from parietal-occipital cortex, was evaluated in freely moving awake mice for 24 hours while the effect of valporate (250 mg/kg), ethosuximide (200 mg/kg), carbamazepine (30 mg/kg) and a Ca++ antagonist nimodipine (10 mg/kg) for 3 hours after treatment. The most active antiepileptic drug was chosen for memory tasks (object recognition to test episodic memory and conditioned taste aversion (CTA) to test visceral memory). Motor integrity was also evaluated in an activity cage for 30 min.
During 24-h recording ET mice showed an EEG characterized by a significant increase of spikes compared to WT mice, reminiscent of an epileptic EEG profile (even if no behavioural seizures were shown). All the drugs blocked spike activity but with different potency (valproate>ethosuximide>carbamazepine>nimodipine). Associative memory was impaired in ET mice compared to WT as shown by the reduced ability to discriminate the familiar from the unfamiliar object and to associate a malaise, induced by subcutaneous treatment with LiCl (63 mg/kg), to a flavored acid solution (HCl 0.008M). Treatment with valporate, given 20 min before each test, fully restored cognitive function in ET mice.
In conclusion, these findings demonstrate that decreased brain levels of SNAP-25 increase brain excitability and impair associative memory. Valproate treatment restored both EEG alterations and memory associative deficit leading to a possible association between SNAP-25 and epilepsy.
1) Verderio C et al (2004) - Neuron vol 41(4):599-610.
2) Pozzi D et al (2008) - Proc Natl Acad Sci USA vol 105(1):323-8.
3) Corradini I et al (2009) - Ann N Y Acad Sci vol 1152:93-9.
4) Shatskikh TN et al (2006) - Epilepsy Behav vol 9(4):549-56.