Impaired feedforward inhibition of the thalamocortical projection in epileptic Ca2+ channel mutant mice, tottering.

The tottering (tg) mice have a mutation in the CaV2.1 (P/Q-type) voltage-dependent Ca2+ channel alpha(1)2.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at approximately 3 weeks of age and persists throughout life. Similarities in EEG and sensitivity to antiepileptic drugs suggest that tg mice are a good model for human absence epilepsy. Although imbalance between excitatory and inhibitory activity in the thalamocortical network is thought to contribute to the pathogenesis of absence epilepsy, the effect of the mutation on thalamocortical synaptic responses remains unknown. Here we showed imbalanced impairment of inhibitory synaptic responses in tg mice using brain slice preparations. Somatosensory thalamocortical projection makes not only monosynaptic glutamatergic connections but also disynaptic GABAergic connections, which mediate feedforward inhibition, onto layer IV neurons. In tg mice, IPSC amplitudes recorded from layer IV pyramidal cells of the somatosensory cortex in response to thalamic stimulation became disproportionately reduced compared with EPSC amplitudes at later developmental stages (postnatal days 21-30). Similar results were obtained by local stimulation of layer IV pyramidal neurons. However, IPSC reduction was not seen in layer V pyramidal neurons of epileptic tg mice or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (postnatal days 14-16). These results showed that the feedforward inhibition from the thalamus to layer IV neurons of the somatosensory cortex was severely impaired in tg mice and that the impairment of the inhibitory synaptic transmission was correlated to the onset of absence epilepsy.

Influence of dopamine on ventrolateral thalamic inputs in cat motor cortex.

Neuronal activity in several brain regions is modulated by dopaminergic inputs. When single neuronal activity/20 trials of single-pulse ventrolateral thalamic (VL) stimulation was extracellularly recorded in the in vivo, anesthetized cat motor cortex, iontophoretic application of dopamine (DA) elicited either suppression or, in a fewer instances, facilitation of evoked unitary responses. The predominant inhibition exerted by DA appeared to be consistent for successive trials, and a D(1), D(2), and D(1)/D(2) receptor antagonist restored the effect, thereby reflecting a possible coexistence of two DA receptors. By contrast, only a fewer neurons' response to DA displayed facilitation, which was not attenuated by DA antagonists. Moreover, subsequent trials with receptor agonist and antagonists induced inconsistent effects. Except for the jitters, single unit spikes showed invariant latency, which was constant during all recording parameters, and the mean latency remained unchanged. The modulatory effects mediated by DA did not reveal any substantial difference between short- and long-latency responses. Both pyramidal tract neurons and non-pyramidal tract neurons, determined on the basis of antidromic potentials from the pyramidal tract, responded to DA essentially in a similar manner. It appears that DA overall inhibits cat motor cortical neuronal activity in response to VL inputs. We propose that such DAergic inhibition of thalamocortical excitation in the motor cortex could be critical for ongoing sensorimotor transformation.