Kestutis Gurevicius

Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice.

Mice carrying mutated human APPswe and PS1 (A246E) transgenes (A/P mice) show age-dependent memory impairment in hippocampus-dependent tasks. Moreover, the mice show normal learning in the water maze within a day but impairment across days. We recorded LTP in a slice preparation (CA1) and in chronically implanted animals (dentate gyrus, or DG) at 17-18 months of age. The genotypes did not differ in the basal synaptic transmission. Also, LTP induction and its maintenance over 60 min did not differ between A/P and control mice. However, the fEPSP enhancement in vivo decayed to 77% of its maximum in 24 h in A/P mice while remaining at 96% in control mice. The time course of the LTP decay in the A/P mice corresponds to their behavioral impairment and indicates that Abeta accumulation in the dentate gyrus may interfere with the signal transduction pathways responsible for memory consolidation.

Role of α-synuclein in synaptic glutamate release

Abstract Defective mobilization of dopamine from the reserve pool has been reported in both α-synuclein knockout mice (KO) and pPrp-A30P transgenic mice. The present study extends these findings to glutamate release. Standard hippocampal slices were prepared from KO, pPrp-A30P, and C57BL/6J wild type (WT1) mice, as well as from mice with transgenic overexpression of wild type human α-synuclein (pSyn-hASY) and their negative littermates (WT2), and field responses were measured in CA3 in response to mossy fiber stimulation. The input/output curves indicated no differences in basal synaptic transmission between groups. Paired-pulse facilitation was significantly weaker in both transgenic α-synuclein lines and KO mice compared to their controls. High-frequency stimulation induced LTP only in transgenic mice. Frequency-facilitation was absent in KO mice and different from other mouse lines. These findings support the idea that lack of α-synuclein impairs mobilization of glutamate from the reserve pool. However, transgenic expression of A30P mutated or wild type α-synuclein does not appear to prevent endogenous mouse α-synuclein to carry out this function.

Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels

Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimers disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored.

Enhanced cortical and hippocampal neuronal excitability in mice deficient in the extracellular matrix glycoprotein tenascin-R.

Mice deficient in the extracellular matrix protein tenascin-R (TN-R-/- mice) show several indices of impaired perisomatic inhibition in hippocampal slices. The present study examined electroencephalograms (EEGs) and auditory-evoked potentials (AEPs) in freely moving TN-R-/- and wild-type control mice, focusing on the hippocampal CA1 field and cerebral cortex. TN-R-/- mice expressed normal high-frequency oscillations (ripples) in CA1 and only a slight reduction of peak theta frequency. In contrast, their hippocampal gamma oscillations were significantly enhanced in amplitude. Also, the amplitude of the cortical EEG of TN-R-/- mice was increased over a wide frequency range. The amplitude of cortical and, to a lesser degree hippocampal, AEPs was clearly enhanced in TN-R-/- mice. In addition, response habituation to repeated sound stimuli was significantly attenuated in TN-R-/- mice. These findings indicate that tenascin-R is involved in the regulation of certain inhibitory mechanisms in the intact brain.

Alteration of cortical EEG in mice carrying mutated human APP transgene

Transgenic mice expressing human APPswe and PS1-A264E mutations mimic certain neuropathological features of Alzheimers disease (AD). These mice have elevated levels of the highly fibrillogenic amyloid beta1-42 peptide (Abeta42) and develop amyloid plaques around the age of 9 months. Our aim was to find whether these transgenic mice differ electrophysiologically from non-transgenic mice and whether the alteration in EEG activity progresses with the accumulation of Abeta. The APP/PS1 mice had reduced cortical theta activity and enhanced beta and gamma activity, but these changes were not age-dependent. APP single mutant mice had similar EEG alterations in theta, beta and gamma bands as APP/PS1 double mutant mice while PS1 single mutant mice did not differ from non-transgenic controls. Insoluble Abeta40 and Abeta42 levels were robustly increased in APP/PS1 double mutant mice and insoluble Abeta40 moderately increased also in APP single mutant mice. Soluble Abeta42 was found in all APP mutant mice but also in lower concentrations in PS1 single mutant mice. Plaques were deposited in 13-month-old APP/PS1 double mutant mice but not in 8-month-old double mutant or 13-month-old single mutant mice. We conclude that the alteration of EEG activity in APP/PS1 double mutant and APP single mutant mice is related to their APP genotype rather than to deposition of beta-amyloid in the brain.

Aging and α-synuclein affect synaptic plasticity in the dentate gyrus

Although intracellular accumulation of α-synuclein (α-syn) is a characteristic pathological change in Parkinson’s disease, Lewy body dementia and Alzheimer’s disease, the normal function of this presynaptic protein is still unknown. To assess the contribution of α-syn to synaptic plasticity as well as to age-related synaptic degeneration in mice, we compared adult and aged mice overexpressing mutated (A30P) human α-syn with their nontransgenic littermates using behavioral tests and electrophysiological measures in the dentate gyrus. We found decreased basal synaptic transmission and paired-pulse facilitation in the perforant path-dentate granule cell synapses of aged mice. In addition, α-syn accumulation in aged A30P mice but not in aged wild-type mice led to long-term depression of synaptic transmission after a stimulation protocol that normally induces long-term potentiation. These findings suggest that overexpression of mutated α-syn exacerbates the aging process and leads to impaired synaptic plasticity.

Genetic Ablation of Tenascin-C Expression Leads to Abnormal Hippocampal CA1 Structure and Electrical Activity In Vivo

Despite evidence that the extracellular matrix glycoprotein tenascin‐C (TNC) is implicated in brain development and plasticity, its roles in the intact adult brain are unknown. Here we report that spontaneous local field potential (LFP) activity in freely moving adult TNC‐deficient mice is abnormal. The power of cortical and hippocampal theta and gamma oscillations was enhanced in comparison to wild‐type mice. The alteration in hippocampal gamma rhythm was subfield specific, such that CA1 gamma was accentuated while dentate gyrus gamma was normal. Similar to LFP, synaptic transmission and plasticity at perforant path synapses in the dentate gyrus were unaffected by the mutation. Morphological analyses revealed a subfield‐specific reduction in the CA1 volume and a reduction in the numbers of somatostatin‐positive interneurons in the hippocampus as potential structural substrates of the observed functional aberrations. These findings indicate a role for tenascin‐C in structural organization of the CA1 hippocampal subfield and in shaping neural activity.

Increased Cortical and Thalamic Excitability in Freely Moving APPswe/PS1dE9 Mice Modeling Epileptic Activity Associated with Alzheimer's Disease

Amyloid precursor protein transgenic mice modeling Alzheimers disease display frequent occurrence of seizures peaking at an age when amyloid plaques start to form in the cortex and hippocampus. We tested the hypothesis that numerous reported interactions of amyloid-β with cell surface molecules result in altered excitation-inhibition balance in brain-wide neural networks, eventually leading to epileptogenesis. We examined electroencephalograms (EEGs) and auditory-evoked potentials (AEPs) in freely moving 4-month-old APPswe/PS1dE9 (APdE9) and wild-type (WT) control mice in the hippocampus, cerebral cortex, and thalamus during movement, quiet waking, non-rapid eye movement sleep, and rapid eye movement (REM) sleep. Cortical EEG power was higher in APdE9 mice than in WT mice over a broad frequency range (5-100 Hz) and during all 4 behavioral states. Thalamic EEG power was also increased but in a narrower range (10-80 Hz). Furthermore, APdE9 mice displayed augmented cortical and thalamic AEPs. While power and theta-gamma modulation were preserved in the APdE9 hippocampus, REM sleep-related phase shift of theta-gamma modulation was altered. Our data suggest that at the early stage of amyloid pathology, cortical principal cells become hyperexcitable and via extensive cortico-thalamic connection drive thalamic cells. Minor hippocampal changes are most likely secondary to abnormal entorhinal input.

Early Retinal Function Deficit without Prominent Morphological Changes in the R6/2 Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HD-related pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HD-related pathology. However, due to functional deficits in the rod- and cone-pathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice.

Increased hippocampal and cortical beta oscillations in mice deficient for the HNK-1 sulfotransferase.

The HNK-1 carbohydrate is detectable in perineuronal nets around inhibitory neurons in the hippocampus and neocortex. To address the functional contribution of HNK-1 to interneuron function in the adult brain, we recorded EEG and auditory-evoked potential in freely moving mice deficient for HNK-1 sulfotransferase (ST-/- mice) and in wild-type littermates. While ST-/- mice displayed normal theta oscillations, both cortical and hippocampal oscillations within the beta range were enhanced, and gamma oscillations showed an opposite trend. ST-/- mice had amplitudes of auditory-evoked potentials similar to control mice, but the latencies of their hippocampal responses were shorter. Morphological analysis revealed a decreased density of parvalbumin-positive interneurons in the hippocampal CA3 subfield of ST-/- mice, which may contribute to the observed changes in networks oscillations. These findings reveal alterations in ST-/- mice that differ from EEG abnormalities of mice deficient in the HNK-1 carrier molecule tenascin-R.