Neuronal L-type calcium channels have been implicated in pain perception and neuronal synaptic plasticity. To investigate this we have examined the effect of disrupting the gene encoding the Ca_V1.3 (α1D) α subunit of L-type Ca²⁺ channels on neurological function, acute nociceptive behavior, and hippocampal synaptic function in mice. Ca_V1.3 α1 subunit knockout (Ca_V1.3α1^−/−) mice had relatively normal neurological function with the exception of reduced auditory evoked behavioral responses and lower body weight. Baseline thermal and mechanical thresholds were unaltered in these animals. Ca_V1.3α1^−/− mice were also examined for differences in N-methyl-d-aspartate (NMDA) receptor-dependent (100 Hz tetanization for 1 s) and NMDA receptor-independent (200 Hz in 100 μM DL-2-amino-5-phosphopentanoic acid) long-term potentiation within the CA1 region of the hippocampus. Both NMDA receptor-dependent and NMDA receptor-independent forms of long-term potentiation were expressed normally. Radioligand binding studies revealed that the density of (+)[³H]isradipine binding sites in brain homogenates was reduced by 20–25% in Ca_V1.3α1^−/− mice, without any detectable change in Ca_V1.2 (α1C) protein levels as detected using Western blot analysis. Taken together these data indicate that following loss of Ca_V1.3α1 subunit expression there is sufficient residual activity of other Ca²⁺ channel subtypes to support NMDA receptor-independent long-term potentiation and some forms of sensory behavior/function.